LARGE-SCALE CENTERS FOR THE PROTEIN STRUCTURE INITIATIVE
RELEASE DATE: April 1, 2004
RFA Number: RFA-GM-05-001
EXPIRATION DATE: October 16, 2004
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of General Medical Sciences (NIGMS)
(http://www.nigms.nih.gov)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.859
LETTER OF INTENT RECEIPT DATE: September 10, 2004
APPLICATION RECEIPT DATE: October 15, 2004
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Additional Review Considerations
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The National Institute of General Medical Sciences (NIGMS) encourages
applications for cooperative agreements to support large-scale
structural genomics research centers for the determination of unique
protein structures. These centers will form one component of the
Protein Structure Initiative (PSI) Research Network, the integrated
second, or production, phase of the PSI (PSI-2). Each large-scale
center must perform all tasks of structural genomics in a high-
throughput operation to produce a large number of unique protein
structures to meet the PSI-2 goals for structural coverage of sequenced
genes. Each large-scale center must also develop technologies and
methodologies that will make the production and structural
determination of proteins less expensive, more efficient, and more
likely to be successful.
RESEARCH OBJECTIVES
A. Background
With the completion of the sequencing of the genomes of human and other
organisms, attention has focused on the functional characterization of
large sets of proteins. The availability of sequence data,
computational analyses of protein sequence families, technological
developments in x-ray crystallography and nuclear magnetic resonance
(NMR) spectroscopy, and the growing impact of structural biology on
biomedical research has led to an international effort to determine
protein structures on a large scale and to the emerging field of
structural genomics. The NIGMS played a major role in the early
planning for this field and in 1999 organized a national program, the
Protein Structure Initiative (PSI).
The long-range goal of the PSI is to make the three-dimensional atomic
level structures of most proteins easily obtainable from knowledge of
their corresponding DNA sequences. The PSI plans to accomplish this
goal by the creation and distribution of a large collection of protein
structures. Structural studies by X-ray crystallography and NMR in a
high throughput mode of operation will achieve a systematic sampling of
major protein families. These experimentally determined structures
will be used as templates for computational modeling of related protein
homologs to produce structural coverage of a majority of sequenced
genes. As it grows, the PSI collection of structures is expected to
have a significant impact on biological and medical research, in a way
similar to the human genome project. These structures will help
researchers discover the functions of proteins, design better
experiments, and study key biomedical problems such as protein folding,
structure prediction, and the organization of protein families and
folds. In addition, the results of these studies will be useful for
faster identification of promising new structure-based medicines,
better therapeutics for treating both genetic and infectious diseases,
and development of technology and methodology for protein production
and crystallography. For more details about the PSI's goals,
organization, and benefits, see the PSI mission statement at:
http://www.nigms.nih.gov/psi/mission.html. Additional information
about the PSI can be found under the links listed below.
Prior to initiating the PSI, the NIGMS organized three workshops
composed of experts from the scientific community to examine
feasibility, constituent tasks, goals, planning, and target selection
for this project. There was general agreement on technical feasibility
due to advances in the development of high-throughput expression
systems, protein purification, sample preparation, and structure
determination by X-ray crystallography and NMR. It was agreed that all
tasks could be organized on the large scale required. A summary of
these meetings can be found on the NIGMS web site at:
http://www.nigms.nih.gov/psi/. Following these workshops and
discussions by the National Advisory General Medical Sciences Council
(NIGMS Council), the PSI was initiated.
The pilot phase of the PSI began in 2000 with a 5-year program for the
development of research centers. The principal goal of the pilot phase
is the development of a structural genomics pipeline for the
determination of unique protein structures in a high-throughput
operation. This program was designed to test all facets and strategies
for the subsequent production phase of the PSI. Protein targets are
chosen as representatives of sequence families and thus provide broad
structural coverage of sequenced gene products. Most of the nine pilot
centers use the 30% sequence identity rule (less than 30% of the
sequence is identical to the sequence of a known structure) and/or
profile methods to identify targets for unique protein structures.
Each pilot center also includes other criteria relevant to feasibility
and its own scientific mission: biological function, medical
relevance, etc. Over 70% of the structures produced by the PSI pilot
centers are unique by the 30% sequence identity rule. Duplication of
effort is avoided by the public listing of all protein targets (See
Special requirement B.1). Major investments in technology and
methodology development at the nine PSI research centers are making
each step of experimental structure determination more efficient, less
expensive, and more likely to succeed. More information on the nine
PSI pilot centers and the technological developments can be found at
the PSI website: http://www.nigms.nih.gov/psi/. In addition to the PSI
pilot research center program, the Institute has supported the
development of methodology and technology underpinning the structural
genomics through two research programs for individual investigators,
program projects, and small business grants (PA-99-116 and PA-99-117,
http://grants.nih.gov/grants/guide/pa-files/PA-99-116.html and
http://grants.nih.gov/grants/guide/pa-files/PA-99-117.html). The
NIGMS PSI program has also sponsored and/or organized numerous
workshops for the pilot centers to address technical bottlenecks to
high-throughput operation. These workshops covered the following:
general structural genomics bottlenecks, x-ray diffraction, NMR,
protein production, data deposition, protein production and
crystallization, data management, homology modeling, and target
selection. Researchers in the pilot projects have used a diversity of
approaches to overcome these problems, and progress has been reported
in the workshops, scientific meetings, and various publications.
Reports of these workshops are available at the PSI website at:
http://www.nigms.nih.gov/psi/meetings.html.
B. Programmatic Summary
Analyses of the results of the pilot research centers by the NIGMS
staff, PSI Advisory Committee (See Special requirement A.8), and the
NIGMS Council, have led to the following summary:
1. Structural genomics pipelines can be constructed and scaled-up.
This process takes considerable investment in robotic instruments,
laboratory and data management systems, staff training, etc. Scaling-
up takes time and care but can be accomplished.
2. High-throughput operation works for many proteins and has led to
many successful determinations of protein structures. The development
and incorporation of robotic instruments, standard protocols, and
laboratory/data management systems have made notable impact on cost,
efficiency, success, and time in the passage from DNA sequence to
structure. Thus far, most of the proteins that have been solved are
the low-hanging fruit - easy to express and purify.
3. The structural genomics approach of choosing multiple targets is
successful. Although the automated approaches are effective, the
chance of successfully determining a structure for a given target is
still not high. However, with multiple targets available for most
protein families, the likelihood of obtaining the structure of one
family representative is significantly increased.
4. Bottlenecks remain for some proteins, such as membrane proteins,
proteins from human and other higher eukaryotes, and small protein
complexes. These challenging proteins are significantly more difficult
to produce and crystallize.
5. A coordinated, 5-year target selection policy must be developed.
The pilot phase approach has worked well, with few duplicate structures
produced and most of the structures being unique family representatives
at the time of deposition. Additional coordination on target selection
is called for in PSI-2 since a higher level of protein structure output
is expected.
6. Homology modeling methods need improvement. Steady improvement has
been noted in the methods for comparative homology modeling. However,
major improvement is needed to improve the accuracy of the models and
decrease the number of experimental structures that need to be
determined.
7. The impact of the PSI to the broad scientific community should be
increased. Benefits from the PSI structures and technologies are
growing, but more activities are needed to utilize these results fully.
C. Objectives
The purpose of this RFA is to announce support for large-scale centers
for the high-throughput production of unique protein structures by X-
ray crystallography and NMR methods. These research centers will be
one component of the PSI Research Network in structural genomics.
PSI Research Network: The production phase, PSI-2, will consist of an
interacting network with four components.
o In the first component, large-scale research centers will perform
every step of the structural genomics process starting with DNA
sequences and leading to the high throughput determination of a large
collection of unique protein structures. These large-scale PSI
research centers are the subject of this announcement (GM-05-001) and
are described in detail below.
o The second component of the PSI Network will focus on the
development of new methods, technology, approaches, and ideas for
protein production and structure determinations for especially
challenging proteins, including membrane proteins, small protein
complexes, and proteins from human and other higher eukaryotes. These
specialized centers will be supported by NIGMS and the National Center
for Research Resources (NCRR) and are described in a separate
announcement (GM-05-002).
o The third component of the PSI Network will consist of specialized
centers that determine protein structures from microorganisms, tissues,
or organ systems related to specific diseases. This third component of
the PSI Network is being considered as an activity of the NIH
Structural Biology Roadmap initiative.
o The fourth component of the PSI Network is the development and
operation of the PSI Network Knowledge Base. This component will serve
as an interface, linking data from the PSI research centers with the
Protein Data Bank (PDB) and other major databases related to the PSI.
This resource will be a central information hub for the PSI Research
Network. It will analyze and organize the results from a structural
genomics perspective. The NIGMS staff is currently developing a
mechanism for supporting this component.
o Other related research projects can be added to the PSI Network if
determined appropriate by the Director of the PSI Network.
Features of large-scale centers: The large-scale research centers will
operate high-throughput structural genomics pipelines for the protein
production and structure determination that is necessary for this
production phase. The large-scale centers should contain all of the
constituent tasks of structural genomics (See section below) and should
demonstrate the ability to accomplish these in a high-throughput
operation. Effective plans for management and administration of the
research centers are crucial. Attention should be paid to costs,
success rates, and efficiency. Rapid release of data into the public
databases is required. Continuing development of technologies and
methodologies is also required. Target selection will focus on
representatives of large protein families to maximize the number of
structures that can be modeled from this set of experimental
structures, as described below. Each of these large-scale research
centers must solve a large number of unique protein structures each
year. This number and appropriate milestones for each center will be
determined by the NIGMS staff, following discussions by the Steering
Committee and members of the PSI Advisory Committee. For the easier
targets (the "low-hanging fruit") this number is expected to be about
200 unique structures per year per center. This goal seems achievable
based on the progress demonstrated in the pilot phase in developing
protocols and automation for high-throughput operation for many protein
targets. These large-scale centers will also serve as centralized
facilities capable of providing structural information quickly in
response to critical biological and medical problems.
Constituent task of the large-scale centers:
1. Family classification and target selection: There are several
schemes of protein sequence clustering for parsing proteomes into
protein families and for choosing protein targets for structural
genomics projects. Target selection will continue to emphasize the
selection of proteins as representatives of sequence families to
rationally search for unique protein structures. In PSI-2 targets will
be selected to maximize structural coverage of most sequenced genes, as
described below.
2. Generation of protein for biophysical analyses: The center
applicants will be expected to demonstrate the capability for high
throughput cloning, expression, and purification systems to produce
large quantities of target proteins in a form suitable for biophysical
studies. Emphasis should be on rates of success, efficiency, and cost
savings.
3. Sample preparation for structural studies: This crucial
experimental task has seen significant progress, with significant
improvement in the ability of structural biologists to crystallize
proteins and label protein samples for NMR studies. Applicants must
demonstrate their experience and plans for the preparation of samples
for structure determinations in a high- throughput mode.
4. Challenging protein targets: Some classes of proteins are still not
amenable to high-throughput operations. These include membrane
proteins, protein complexes, and proteins from human and other higher
eukaryotes. The PSI-2 large-scale centers are expected to include
challenging proteins in their target selection plans and to plan for an
innovative subproject focused on the production and structural
determination of one or more classes of these proteins.
5. Structure determination: High-resolution structure determination is
becoming straightforward for many protein samples. Crystallography has
benefited from the almost universal use of synchrotron beamlines
coupled with new detectors, cryocrystallographic techniques, multiple-
wavelength anomalous diffraction techniques, and advanced computational
systems for rapid data collection, processing, and model building. New
NMR methods and higher field instruments have increased the size of
proteins that can be solved by this technique. The structure
determination component should be the nucleus of a structural genomics
research center. Applicants for the PSI-2 large-scale research centers
must have considerable expertise and resources in either or both of
these techniques and are expected to demonstrate their access to state-
of-the-art synchrotron and/or NMR facilities. The NIGMS is currently
developing additional beamlines at several synchrotron facilities and
will likely be able to make additional beamtime available to general
users and research centers funded by this RFA within the next few
years. However, the PSI-2 research centers are expected to present
their own plans for data collection and structure determinations.
6. Analyses and dissemination of results: The research centers will be
expected to analyze their structures by computational techniques for
biomedical significance, including functional characterization and
evolutionary and structural relationships. Since the goal of this
initiative is to add to the body of knowledge of protein structure,
timely release and dissemination of results are crucial. These results
include information on strategies for target selections, status of
these proteins in the structural genomics pipeline, technological and
methodology findings, high throughput approaches, efficiency, and cost
analyses. The research centers are required to have plans for timely
deposition of coordinates and related data into the Protein Data Bank
(PDB) and other relevant public databases, consistent with NIH policies
and PSI programmatic goals. (See Special requirements B.1)
7. Management and administration: With several components that are
interdependent, management and administration of the center are
crucial. In addition to the usual administrative requirements, the
leadership of each research center must direct the research and make a
wide range of decisions about subcontracts, equipment purchases,
staffing, standard protocols, pipeline priorities and protocols, etc.
Special PSI requirements, such as cooperative agreement commitments,
annual reports, attendance at PSI meetings, participation of minority
scientists and students, outreach to the scientific community, research
training, intellectual property, participation in the PSI Network,
etc., must be incorporated by the applicant into the organization of
each research center.
Target selection for PSI-2: Since its inception in 1999, the general
principle for target selection for the Protein Structure Initiative has
focused on representatives of protein sequence families for which there
are no known structures. This approach leads to the determination of
unique, non-redundant protein structures and is the policy followed in
the PSI pilot phase. Although the target selection policy for PSI-2
begins with this general principle, a more specific policy is required
for this subsequent and more focused phase. The NIGMS staff has
determined that the best specific strategy for target selection for the
PSI Network and PSI-2 is to concentrate on large protein families in
order to provide the broadest possible structural coverage of sequenced
genes. A secondary goal aims directly at biomedical impact with
projects focusing on specific pathways, organisms, systems, etc.
These conclusions were reached through a lengthy planning process.
Prior to the PSI pilot RFA, the NIGMS held a workshop on target
selection. More recently, in November 2003, another workshop focused
on this issue
(http://www.nigms.nih.gov/psi/meetings/target_selection.html ) as well
as a meeting with the PSI Advisory Committee in December 2003
(http://www.nigms.nih.gov/psi/meetings/psi-advisory-centers.html ). At
these meetings, most participants agreed on the strategy for structural
coverage of sequenced genes by focusing on structural determination of
large protein sequence families. Experts from genomic and other
biomedical fields discussed the appropriate balance of genomic coverage
and biomedical impact. A crucial issue in these discussions was the
appropriate level of the detail, or granularity, of structural coverage
of sequenced genes. At coarse granularity, sequence homology
comparisons are carried out by PSI-BLAST or other profile-based methods
to produce protein families with distant evolutionary links. This
parsing leads to fewer families, each with more members. As a result,
fewer experimental structures will be needed for structural coverage of
sequenced genes, and the structural models generated will be moderately
accurate for distant homologs in the same family. On the other hand,
structural coverage at fine granularity, chosen, for example, as 30%
sequence identity, would lead to a larger number of sequence families,
each with fewer members. At this fine granularity, more experimental
structures will be required, and the computational models generated
thereafter would in general be more accurate and suitable for studying
biological function. In this workshop and in discussions with the PSI
Advisory Committee members, the NIGMS Council, and members of the
scientific community, there was general agreement among the
participants of the workshop and meetings that 1) 4-5,000 experimental
structures representing large sequence families would provide
structural coverage at coarse granularity of sequenced genes, 2) this
collection of structures would be a valuable resource for the
biomedical community, 3) this project should be the primary goal for
PSI-2, and 4) this project could be achieved in the 5-year term of PSI-2.
Most of the scientists attending these meetings and workshops agreed on
another mission for PSI-2: the focus on specific biomedical research
problems from a structural genomics approach. The determination of a
collection of unique, non-redundant protein structures for specific
pathways, organisms, and/or groups of proteins was seen to have high
scientific value. For this secondary goal, it was suggested that each
center plan and carry out a research project with a significant
biomedical theme, choosing appropriate protein targets for structural
coverage at either fine or coarse granularity. The structural genomics
pipeline would be utilized for production and structural determination
of the proteins chosen to address this scientific problem. In
addition, other protein targets could be nominated by members of the
scientific community as part of this biomedical theme component of PSI-2.
Target selection goals for the large-scale centers: Following these
meetings and workshops and other discussions with members of the
scientific community, the NIGMS staff has determined that the target
selection policy for PSI-2 should reflect a balance between structural
coverage of sequenced genes and the exploration of biomedically
important pathways and systems, as described in the previous
paragraph. As the facilities that will be charged with carrying out
these goals, each large-scale center must develop plans for the
following:
Target selection goal #1. Complying with the decisions of the Steering
Subcommittee on Target Selection for structural coverage of a majority
of sequenced genes by the determination of representative structures of
large protein families at coarse granularity (See Special requirement
A.7). This part should encompass the majority of the center’s effort.
Each applicant must identify groups of proteins (e.g., pan-genomic or
multiple prokaryotes and/or eukaryotes) that the center will consider
in the selection of targets and explain why they are appropriate for
high-throughput operation and large-scale output and for meeting the
structural coverage goals of the PSI Network.
Target selection goal #2. Carrying out a structural genomics research
project with a significant biomedical theme. Each center must propose
a biomedical research project that leads to a collection of unique,
non-redundant protein structures and structural coverage at fine or
coarse granularity of protein families from specific pathways,
organisms, and/or groups of proteins of high scientific value. Protein
targets must be selected by each center for high throughput protein
production and structure determination to address this scientific
problem. The applicant must provide details on goals, plans, and
impact of the project.
Target selection goal #3. Complying with the decisions of the
Subcommittee on Target Selection for structural coverage at fine or
coarse granularity of proteins that are proposed by the scientific
community to the PSI Network. The effort toward this activity should
be approximately equal to that of the second part.
After the initiation of PSI-2, the Steering Committee and the PSI
Advisory Committee will meet jointly with the NIH staff to determine
how to carry out target selection for the PSI Network. Further
refinement of the target selection criteria by these same groups will
occur on a regular basis as the PSI-2 project matures. Each research
center should have plans for target selection of proteins for
experimental structural determination to fulfill the PSI objectives as
stated above. Each center must participate in all discussions on
target selection and have plans for completing the work outlined by the
Steering Committee.
Technology development: Advances in technology and methodology during
the PSI pilot phase have permitted the establishment of a structural
genomics pipeline approaching an industrial scale. In particular,
average costs per structure have decreased markedly, but further
reductions to about $50,000 total costs per structure are essential for
meeting the PSI-2 goals. Success rates of each component of the
pipeline have also improved, but are not sufficient. The numerous
facets and difficulties of each step of the production and
determination of unique protein structures require continued technology
and methodology development during the production phase. Existing
equipment, standard protocols, and laboratory/data management systems
can be scaled up, but further technical breakthroughs and innovation
are necessary for reaching the long-term goals of the PSI. In PSI-2,
the large-scale centers must continue methodology and technology
development to improve all elements of the structure genomics pipeline.
MECHANISM OF SUPPORT
This RFA will use NIH Specialized Center (U54, Cooperative Agreement)
award mechanism. As an applicant, you will have the primary
responsibility for planning, directing, and executing the proposed
project. This RFA is a one-time solicitation. The anticipated award
date is July 1, 2005. This RFA uses just-in-time concepts. This
program does not require cost sharing as defined in the current NIH
Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2003/master_list.htm .
The NIH U54 is a cooperative agreement award mechanism. In the
cooperative agreement mechanism, the Principal Investigator retains the
primary responsibility and dominant role for planning, directing, and
executing the proposed project, with NIH staff being substantially
involved as a partner with the Principal Investigator, as described
under the section "Cooperative Agreement Terms and Conditions of
Award." Plans for this program beyond the 5-year award period are
indefinite and will be considered by the Institute staff with the
advice of the NIGMS Council. Applicants may submit applications in
response to this RFA for large-scale centers (GM-05-001) and the RFA
for specialized technology centers(GM-05-002) and the RFA for centers
for protein structures related to disease (if this
RFA is published). If an applicant submits to one or more, the overlap
must be clearly noted. Only one award will be made to any applicant.
FUNDS AVAILABLE
The NIGMS intends to commit up to $60 million in FY2005 to fund up to 5
new large-scale centers in response to this RFA. An applicant may
request a project period of up to 5 years and a budget for the first
year for up to $12 million total costs. This cap must include all
costs, such as equipment and indirect costs for subprojects. Annual
cost-of-living increases in future years must not exceed 3%. Because
the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size and
duration of each award will also vary. Although the financial plans of
NIGMS provide support for this program, awards pursuant to this RFA are
contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
Post-award management: During the course of the grant period, both
computational and experimental technologies are expected to improve,
and the rate of progress and focus of work supported by the grant may
change. It is expected that the Principal Investigator will make any
necessary adjustment in scientific direction to accommodate the
expected scale-up and changing environment. The NIGMS staff must be
kept informed of any significant changes. In order to ensure that the
project remains focused on appropriate goals, incorporates new
technological advances, and makes sufficient progress, scientific and
programmatic visits to the grantee will be conducted at a frequency to
be determined by NIGMS staff. In addition, benchmarks for progress may
be negotiated annually.
The NIGMS may include outside consultants in the annual progress review
and reduce or withhold funds for failure to meet milestones agreed upon
by grantees and NIH staff. A report by the NIGMS program director on
each research center's progress and any recommendations to modify
funding will be made annually to the National Advisory General Medical
Sciences Council.
ELIGIBLE INSTITUTIONS
You may submit an application if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of state and local governments
o Eligible agencies of the Federal government
o Domestic institutions/organizations
o Foreign institutions are not eligible to apply but are eligible for
inclusion as subcontracts with sufficient justification.
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with his/her
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
A. Special requirements for cooperative agreements
1. Cooperative Agreement Terms and Conditions of Award
The following section represents Terms and Conditions that will be
incorporated into the award statement and will be provided to the
Principal Investigator, as well as to the appropriate institutional
official, at the time of award. The following special terms of award
are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45
CFR Parts 74 and 92 (Part 92 is applicable when State and local
Governments are eligible to apply), and other HHS, PHS, and NIH grant
administration policies:
The administrative and funding instrument used for this program will be
the cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during performance of the
activities. Under the cooperative agreement, the NIH purpose is to
support and stimulate the recipients' activities by involvement in and
otherwise working jointly with the award recipients in a partnership
role; it is not to assume direction, prime responsibility, or a
dominant role in the activities. Consistent with this concept, the
dominant role and prime responsibility for the project as a whole
resides with the awardees.
2. Principal Investigator
The Principal Investigator is the scientist who assembles the project
and is responsible for submitting the application in response to this
RFA and for performance of the project. The Principal Investigator has
the overall responsibility for scientific and technical direction and
for the administration and overall operation of the large-scale PSI
research center. Each PSI award must implement approved plans for the
PSI-2 target selection goals:
Target selection goal #1. Complying with the decisions of the Steering
Subcommittee on Target Selection for structural coverage of a majority
of sequenced genes by the determination of representative structures of
large protein families at coarse granularity.
Target selection goal #2. Carrying out a structural genomics research
project with a significant biomedical theme.
Target selection goal #3. Complying with the decisions of the
Subcommittee on Target Selection for structural coverage at fine or
coarse granularity of proteins that are proposed by the scientific
community to the PSI Network.
The Principal Investigator will:
o Design and direct the large-scale center
o Design and direct the biomedical theme research project (Target
selection goal #2) as described in the application
o Provide goals and milestones for the project consistent with the
PSI-2 goals
o Commit a substantial level of effort to the project
o Participate in the cooperative agreement activities and accept the
PSI-2 regulations, plans, and decisions
o Be a member of the PSI Research Network Steering Committee (See
Special requirement A.6)
o Attend annual meetings of the Steering Committee and participate in
its activities, including setting goals and making future plans
o Participate in the activities of the PSI Network
o Ensure the timely dissemination of information generated by the
research center to the scientific public
o Ensure that the structure coordinates and structure factors are
deposited promptly to the PDB
o Ensure that results and data are collected, maintained, and
transferred to appropriate databases, including the PDB; the Target
Database; and the Protein Expression, Purification, and Crystallization
Database
o Ensure that all appropriate results are provided to the PSI Network
Knowledge Base
o Ensure that the center complies with the intellectual property
policies of the research center, the NIH, and those developed by the
PSI Network
o Ensure that materials generated by the research center are shared
with qualified scientists
o Submit periodic progress reports
o Appoint an External Scientific Advisory Committee of research
scientists not involved in the consortium to provide independent
assessment and advice to Principal Investigator and the research center
o Manage the Center Development Funds, subject to NIH program director
approval.
3. PSI Network Director
The PSI Network Director is an NIH extramural staff individual who has
leadership responsibilities for the management and coordination of the
PSI Network. The PSI Network Director is not a member of the Steering
Committee and does not direct the scientific activities of the PSI
Network centers (whose direction is the responsibility of the Principal
Investigator). The PSI Network Director will also:
o Provide advice to the PSI Network Steering Committee on the overall
direction of the PSI and on meeting the PSI goals and milestones
o Report on the PSI Network activities and progress to the director of
NIGMS, the NIGMS Council, and advisory councils for other participating
NIH institutes and centers
o Appoint members and a chair of the PSI Advisory Committee, following
consultation with the director of NIGMS
o Evaluate and implement the advice of the PSI Advisory Committee and
the PSI Network Steering Committee for allocating NIH support and
revising and setting policy
o Facilitate communication with the scientific community directly
affected by the PSI
o Ensure that the Steering Committee and the PSI Advisory Committee
address issues and concerns raised by the community.
o Call and coordinate meetings of the Steering Committee and the PSI
Advisory Committee
o Select appropriate additional programs to be added to the PSI
Network as non-voting members of the Steering Committee.
4. NIH Program Directors
The NIGMS Program Directors are the extramural staff individuals who
provide normal program stewardship for the PSI Network center awards.
The NIH Program Directors are not members of the Steering Committee and
do not direct the scientific activities of the PSI Network centers
(whose direction is the responsibility of the Principal Investigator).
The NIH Program Directors will also:
o Negotiate milestones and goals on throughput and costs with the
grantees
o Attend all meetings of the Steering Committee
o Prepare annual reports on the progress of PSI-2 research centers
o Provide information to the research center Principal Investigators
on activities and policies of the PSI Network and the NIH
o Recommend appropriate budgets for the research centers, including
withholding or reduction of support for failure to meet milestones
and/or other terms or conditions.
5. NIGMS/NIH Scientific Liaisons
The NIH Scientific Liaisons are representatives of the NIH extramural
staff who serve on the Steering Committee and have substantial
scientific/programmatic involvement in the project that is above and
beyond normal program stewardship. Each of the NIH institutes and
centers supporting a PSI Network center will have one Scientific
Liaison. In addition, one member of the NIGMS staff will serve on the
Steering Committee and the Steering Subcommittee on Target Selection
This position will be named the Scientific Liaison for Target
Selection. The Scientific Liaisons will also:
o Serve as voting members of the Steering Committee and attend all
meetings
o Assume a substantial coordinating role on the Steering Committee
o Make recommendations to the Steering Committee based upon their
knowledge of other, related NIH-supported research and resource
activities
o Facilitate interactions among the Steering Committee, the PSI
Advisory Committee, and NIH staff
o Provide advice and guidance to the Steering Committee to assure that
the PSI project adheres to the NIH/NIGMS rules and regulations
o Take on additional responsibilities as negotiated at the time of
award.
6. Steering Committee
This committee is the main governing body of the Protein Structure
Initiative Research Network. Membership will include the Principal
Investigators of the large-scale centers, the Principal Investigators
of the specialized centers, the NIH Scientific Liaisons, a
representative of the Protein Data Bank, a representative of the PSI
Network Knowledge Base, and other scientists chosen by the above
members. The NIGMS/NIH Scientific Liaisons will serve as voting
members of the Steering Committee and attend its meetings. Total NIH
representation on the Steering Committee will make up no more than 40%
of the voting members. Other members of the NIH staff may also attend
the Steering Committee meetings. The Principal Investigators of other
related structural genomics projects may be added to the Steering
Committee as non-voting members, as determined appropriate by the PSI
Network Director. The Steering Committee will:
o Meet at least annually with the PSI Advisory Committee and the NIGMS
staff to discuss progress of the PSI Network in reaching the goals set
by the NIGMS/NIH staff and Councils and in meeting the needs of the
scientific community
o Elect a non-NIH chair to serve a 2-year term
o Prepare and publish annual reports on progress in meeting milestones
and goals of the PSI
o Develop procedures and policies on PSI Network activities, including
laboratory information management systems, data management and
deposition, publications, reports, etc. for consideration by the PSI
Advisory Committee and the NIGMS Council
o Communicate with the scientific community on scientific and
technological achievements
o Organize and appoint a subcommittee on target selection
o Serve as the body for coordinating and making decisions on target
selection
o Serve as the body for coordinating and making decisions to ensure
meeting the milestones and goals for the production phase of the PSI
o Organize and appoint appropriate subgroups to address related
issues.
7. Steering Subcommittee on Target Selection
This subcommittee will be composed of the Principal Investigators of
the large-scale centers, the Scientific Liaison for Target Selection,
and other representatives as chosen by the Steering Committee. Program
Directors of the Specialized centers will serve as liaisons to the
Steering Subcommittee for target selection. The subcommittee will
coordinate the selection of protein targets among the large-scale
centers. This subcommittee will do the following:
o Elect a non-NIH chair to serve a 2-year term.
o Obtain appropriate scientific and technical assistance for the
various tasks related to target selection
o Incorporate targets chosen by the specialized centers into the list
of targets for the PSI Network
o Develop a list of targets of representatives from large protein
families to meet the PSI-2 goals for structural coverage of sequenced
genes at coarse granularity (Target selection goal #1)
o Develop a list of targets of representative protein families for the
biomedical theme project for structural coverage at coarse or fine
granularity to meet the PSI-2 goals (Target selection goals #2 and #3).
This activity has two parts:
1. Develop a process for soliciting suggestions from the scientific
community for groups of proteins for consideration for structural
coverage at coarse or fine granularity (Target selection goal #3)
2. Develop a process for integrating targets chosen by the large-scale
centers for their biomedical theme projects (Target selection goal #2)
with those from the scientific community (Target selection goal #3)
o Develop a process for utilizing each center’s structural genomics
pipeline for: (1) coarse granular coverage of sequenced genes (60-70%),
(2) fine or coarse granular coverage of the biomedical theme projects
chosen by the center(15-20%), and (3) fine or coarse granular coverage
of the proteins proposed by the scientific community (15-20%)
o Develop a final list of targets for the PSI Network
o Coordinate target selection for protein production and structure
determination at the large-scale centers
o Report to the Steering Committee on these plans for target
selection.
8. PSI Advisory Committee
The PSI Advisory Committee is a working group of the NIGMS Council. It
will advise the Council on the management, progress, and plans for the
PSI. This committee will:
o Meet at least once a year with the Steering Committee and NIH staff
prior to the submission of the annual progress report
o Examine and comment on target selection policy and progress toward
milestones
o Provide advice to the Principal Investigators and Steering Committee
about meeting the PSI goals and plans for future directions
o Raise issues for consideration by the Principal Investigator and the
Steering Committee
o Comment on the appropriateness of the level of NIGMS support to
achieve the goals of the project.
9. Goals and Milestones
The PSI-2 will have annual milestones appropriate to the 5-year goal.
Milestones will be determined through discussions with the Principal
Investigators, Steering Committee, and NIH staff. The milestones and
goals will be refined annually with input from the Steering Committee
and PSI Advisory Committee.
10. Reports
The PSI Network Steering Committee will produce an annual report on the
progress made toward the annual milestones and goal. The report will
be delivered to the NIGMS staff and PSI Advisory Committee within one
month of the annual meeting.
11. PSI Arbitration Panel
A panel formed as needed to review scientific or programmatic
disagreements (within the scope of the award) that may arise between
the PSI Network and the NIH. It will be composed of three members: a
designee of the Steering Committee chosen without NIH staff voting, one
NIH designee, and a third designee with expertise in the relevant area
who is chosen by the other two.
(End of cooperative agreement terms)
B. PSI Research Center special requirements
The NIGMS has adopted several polices that are applicable to these PSI
large-scale research centers. Applicants must present plans to adhere
to the policies, where appropriate.
1. Data Release and Sharing of Results and Materials. The PSI
represents a major scientific endeavor with large amounts of data
generated in the process of protein structure determination. The
primary products of the PSI, structural coordinates, must be deposited
promptly in the PDB, which has served the scientific community for four
decades by providing public access to the annotated structural models.
Other structural results, including, structure factors, must also be
deposited promptly into the PDB. Although guidelines developed by NIH
for research grants
(http://grants.nih.gov/grants/guide/notice-files/not99-010.html)
permit NIH Principal Investigators to deposit coordinates and structure
factors upon publication of results, PSI regulations and programmatic
goals are more stringent and require these depositions upon completion
of the structures. For the start of PSI-2, this will be interpreted as
receipt by the PDB within four weeks of the coordinate refinements.
In addition, dissemination of results of the large-scale research
centers is crucial to the programmatic goals of the PSI, and applicants
should plan on sharing findings and their experiences at the annual
meetings for structural genomics grantees and in other appropriate
forums. This includes information on strategies for target selections,
status of research on these proteins, technological and methodology
findings, high-throughput approaches, efficiency, and cost analyses.
Grantees will be required to develop and maintain a public website
showing the information listed above, as well as providing it in their
annual progress reports. These results must be provided to the PSI
public website, which contains information on the program and technical
and scientific results.
Another database, TargetDB (See TargetDB at http://targetdb.pdb.org/),
was recently developed by PDB with PSI and contains all the PSI
centers targets and weekly progress toward structure determination.
This information should avoid duplicative work and assist planning by
the centers and other structural labs. The current PSI pilot centers
are required to provide these data for uploading each week, and this
policy will continue in PSI-2. TargetDB has increasingly attracted
attention of the scientific community.
The PSI is currently developing a database for deposition of
information on experimental outcome data (both successful and
unsuccessful). These data include genome analysis for protein
clustering and target selection, cDNA cloning, expression vector
construction, protein production and purification, protein biochemical
characterizations, crystallization screening, synchrotron and NMR data
collection, etc. The PSI Research Network centers will be required to
provide plans for the collection, maintenance, and transfer of
experimental results into this central data repository. This database,
named the Protein Expression, Purification, and Crystallization
Database (PepcDB), is under development and will contain information on
these important results and provide a platform for cross-center data
mining to capitalize on the PSI investment (contact Dr. Norvell at
NIGMS for updated information).
In some cases, the proteins and samples generated by these research
centers will need to be pursued by detailed functional studies by
scientists both within and outside the research centers that are beyond
the scope of these awards. The research centers will be required to
provide these materials to appropriate investigators. Currently the
individual pilot centers have the responsibility for distribution of
these proteins and samples, but a centralized repository is being
considered for PSI-2.
In PSI-2, the PSI Advisory Committee and NIGMS staff anticipates the
need for a central resource that interconnects all the data and
resources generated by the PSI with related databases and other
biological information. This resource has been named the PSI Network
Knowledge Base. The PSI research centers will be required to make all
data available for dissemination by the PSI Knowledge Base.
2. Management Plan. The management of a PSI large-scale research
center requires a significant commitment by the senior staff. The
Principal Investigator must devote a substantial effort to the project.
The applicant must propose a management plan that takes into account
the changes that will occur over the 5-year term of the award. If the
requested budget includes Center Development Funds (See Special
requirement B.9), the applicant must explain how decisions on the use
of these funds will be made by the Principal Investigator and the
senior staff of the center.
3. Research Training. Applicants must have plans for research training
activities. One example is the involvement of graduate students and
postdoctoral associates as part of the research staff. Although many
PSI activities involve extensive data collection and therefore might
not be appropriate as research training projects, other activities will
be at the cutting edge of research and thus would be suitable for
graduate thesis research training and for postdoctoral projects.
Another example of a research training activity is the organization of
technical workshops for graduate students and postdoctoral associates
as potential users of the pipeline, materials, and PSI results.
4. Participation of underrepresented minority investigators and
students. The research centers must have plans to promote the
participation of investigators and/or students from underrepresented
minority groups. One example is the organization of summer programs for
faculty and/or students from minority institutions. Another example is
the solicitation of protein targets from faculty at minority
institutions for inclusion in the center’s structural genomics pipeline
and target selection process.
5. Participation of the scientific community. The primary
responsibility of the large-scale PSI centers is the operation of a
structural genomics pipeline to meet the PSI goals on production of
unique protein structures. The deposition of coordinates and other
results are the main service provided to the scientific community, but
the substantial public funds invested in these centers carry an
obligation for further service to scientists interested in the
production of proteins and protein structures. Research center
applicants must have plans for activities for participation of the
scientific community. For example, centers could designate a limited
period of time for the incorporation of special projects from outside
scientists into the structural genomics pipeline. Centers could plan
for short-term courses and technical workshops for potential users of
the pipeline, materials, and PSI results.
6. Intellectual property. NIGMS is committed to making results of
these projects freely available for use by the entire research
community and, therefore, released into the public domain. Applicants
should present plans related to intellectual property rights consistent
with this policy. The NIGMS will monitor its grantees' activities with
respect to patenting the structural results and technology
developments.
The scientific review group will comment, as appropriate, on the plans
and previously demonstrated success for handling intellectual property
issues. Since dissemination of results is a critical aspect of the
PSI, evidence of the commitment to the sharing of research resources
and to effective management of intellectual property issues will be
part of the scientific merit review, as well as an important factor in
the Institute’s decision to make an award. Furthermore, these plans,
after negotiation with the applicant when necessary, will be made a
condition of the award. Evaluation of annual progress reports and of
subsequent renewal applications will include an assessment of the
effectiveness of the sharing of research resources and managing
intellectual property issues.
Plans for sharing of research resources and intellectual property must
make unique research resources readily available for research purposes
to qualified individuals within the scientific community in accordance
with the NIH Grants Policy Statement
(http://grants.nih.gov/grants/policy/nihgps/) and the Principles and
Guidelines for Recipients of NIH Research Grants and Contracts on
Obtaining and Disseminating Biomedical Research Resources: Final Notice,
December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html and
http://ott.od.nih.gov/NewPages/64FR72090.pdf). These documents also
define terms, parties, responsibilities, prescribe the order of
disposition of rights, prescribe a chronology of reporting requirements,
and delineate the basis for and extent of government actions to retain
rights. Patent rights clauses may be found at 37 CFR Part 401.14 and
are accessible from the Interagency Edison web page,
http://www.iedison.gov.
7. External Scientific Advisory Committee. Each research center should
have an external scientific advisory committee of research scientists
not involved in the consortium to provide independent assessment and
advice to the Principal Investigator of each research center and
his/her staff. This committee should be appointed by the Principal
Investigator and meet at least once each year. In order to maximize
the pool of possible reviewers, the potential (or new) members of the
external scientific advisory committee should not be contacted or
selected until after an award has been made.
8. Annual PSI Meeting. The Principal Investigator and appropriate
staff of each PSI large-scale research center will be expected to
attend the PSI annual meeting and workshops to discuss progress and
results.
9. Center Development Funds. This budget item will provide budgetary
flexibility in the development and operation of the structural genomics
pipeline for producing proteins and determining their structures. It
will permit the large-scale centers to make budget changes within a
budget year and to explore innovative ideas and new technologies.
Since reallocation during any budget year between subprojects (often at
different institutions) is difficult, the Center Development Fund may
be needed by a large-scale center to make major changes and move in new
directions. The primary use of these funds must be to support staff
and purchase equipment and supplies related to the pipeline tasks. New
technology and methodology development projects to improve the
structural genomics pipeline are also appropriate. Applicants may
request up to 5% of the total budget annually as a Center Development
Fund. If these funds are requested, the applicant must provide an
explanation of the process that the center will use to determine its
allocation. All expenditures from the Center Development Fund will
require NIH staff approval.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
three areas: scientific/research, peer review, and financial or grants
management issues:
o Direct your questions about scientific/research issues to:
John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13B, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-0533
FAX: (301) 480-2004
Email: norvellj@nigms.nih.gov
o Direct your questions about peer review issues to:
Helen R. Sunshine, Ph.D.
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12F, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-2881
FAX: (301) 480-8506
Email: sunshinh@nigms.nih.gov
o Direct your questions about financial or grants management matters
to:
Ms. Grace Olascoaga
Division of Extramural Activities
National Institute of General Medical Sciences
Building 45, Room 2AN.32E, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-5520
FAX: (301) 480-2554
Email: olascoag@nigms.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by September 10, 2004 to:
John C. Norvell, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13B, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-0533
FAX: (301) 480-2004
Email: norvellj@nigms.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). Applications must
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS)
number as the Universal Identifier when applying for Federal grants or
cooperative agreements. The DUNS number can be obtained by calling
(866) 705-5711 or through the web site at
http://www.dunandbradstreet.com/. The DUNS number should be entered on
line 11 of the face page of the PHS 398 form. The PHS 398 document is
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
SUPPLEMENTARY INSTRUCTIONS:
Special application requirements
The research center should be an integrated, coordinated project, with
various interdependent subprojects that comprise structural genomics as
described above. The subprojects should be organized to be consistent
with the seven components of structural genomics that were listed above
in the section "Research Objectives.C". They must be fully described
and justified. The center must also meet the SPECIAL REQUIREMENTS
B.PSI Research Center Special requirements. Collaborations and
consortia are encouraged. In such collaborations, the respective
contributions should be well integrated into the design of the
application. An overview section should be prepared that includes an
overall description that defines the scope and objectives.
The application should have a face page; abstract; project overview
(which describes the overall program and defines its scope and
objectives); project rationale; subproject descriptions; consolidated
budget; listing of key personnel; subproject budgets; biographical
sketches; investigators' other support; institutional support,
resources and facilities; and letters of collaboration. Applications
should include a separate cover sheet that lists 1)all participants,
including consultants and private sector alliances, 2) all the
institutional affiliations for each participant, and 3) their roles on
the project and whether new or continuing (if applicable). This
requirement will facilitate the review of applications.
The budget should be no greater than $12 million total costs for the
first year, with annual cost-of-living increases (not to exceed 3%) in
subsequent years. The budget should be fully justified and should
include funds for attending the PSI annual meetings, workshops,
Steering Committee meetings, and other PSI meetings. The page limit
for the research plan (including project overview, project rationale,
and subproject descriptions) is 70 pages total.
The application should provide plans and assurances that the center
will:
o Participate in the target selection process of the PSI Network
o Meet the production goals of the PSI Network
o Carry out the work agreed to by the Steering Committee (Target
selection goals #1 and #3)
o Submit data to the PSI Network Knowledge Base.
The application should describe future plans and previously
demonstrated success for:
o Protein family classification and target selection, including their
applicability to the goals of the PSI Research Network
o Producing and determining a large number of unique, non-redundant
protein structures in high-throughput operation
o Methodology and technology development relevant to structural
genomics
o Increasing throughput, efficiency, and success rates and decreasing
costs for producing and determining the structures of proteins
o Operation of a high-throughput structural pipeline that includes all
constituent tasks
o Effective management and administration of a research center or
other large research program (including plans for management of the
Center Development Fund, if this was requested in the budget)
o Sharing of results and prompt placement of data in the public
domain, including deposition of coordinates and structure factors in
the Protein Data Bank
The application should describe plans for:
o Carrying out the scientific goals of the center for the biomedical
theme project designed to focus on protein structures for specific
pathways, organisms, and/or groups (Target selection goal #2)
o Analyses of structures for biomedical significance and dissemination
of results
o Developing annual milestones and evaluations for the center and as a
component of the PSI Network
o Sharing materials generated by this research
o Handling intellectual property issues for the center consistent with
the NIGMS/NIH policies
o Submitting target data and progress to the TargetDB and releasing
cloning, protein production, and crystallization results into PepcDB.
o Providing resource sharing and training to the scientific community.
o Producing and determining unique, non-redundant protein structures
from one or more classes of challenging proteins.
The application should provide data on unique, non-redundant protein
structures that have been solved by the participating investigators
during the past five years. If an investigator has solved few or no
unique, non-redundant protein structures, provide data for all
structures solved for that investigator during the past five years.
These data should include the following information:
o PDB access code and submission date
o Molecular weight
o Most closely related protein in the PDB (give the identity of the
protein and the sequence identity)
o Size of the sequence family (number of proteins that could be
modeled)
o For structures determined by crystallography, give the resolution
and R-factor
o For structures determined by NMR, give the number of meaningful
restraints per refined residue and the rms deviation to the mean
structure for backbone and all heavy atoms
o Information on function and other relevant information.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three signed,
photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application and
all copies of the appendix material must be sent to:
Helen R. Sunshine, Ph.D.
Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12F, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-2881
FAX: (301) 480-8506
Email: sunshinh@nigms.nih.gov
APPLICATION PROCESSING: Applications must be received on or before the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and
funding assignment within 8 weeks.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. However, when a previously unfunded application,
originally submitted as an investigator-initiated application, is to be
submitted in response to an RFA, it is to be prepared as a NEW
application. That is, the application for the RFA must not include an
Introduction describing the changes and improvements made, and the text
must not be marked to indicate the changes from the previous unfunded
version of the application.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by NIGMS. Incomplete applications will not be
reviewed.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by NIGMS in accordance with the review criteria
stated below. As part of the initial merit review, all applications
will:
o Undergo a process in which only those applications deemed to have
the highest scientific merit, generally the top half of the
applications under review, will be discussed and assigned a priority
score
o Receive a written critique
o Receive a second level review by the National Advisory General
Medical Sciences Council
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, provide valuable research resources to the
scientific community, improve the control of disease, and enhance
health. In the written comments, reviewers will be asked to evaluate
the application in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of these goals.
The scientific review group will address and consider each of the
following criteria in assigning the application’s overall score,
weighting them as appropriate for each application.
o Significance
o Approach
o Innovation
o Investigator
o Environment
SIGNIFICANCE: What is the likelihood that the applicant will operate a
successful large-scale, high-throughput research center and meet the
goals of PSI-2? Will be the technology and methodology development of
the research center be significant?
APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of
the project? Are the plans for organization of the center appropriate?
Does the applicant acknowledge potential problem areas and consider
alternative tactics? Are the plans and milestones appropriate?
INNOVATION: Does the project employ novel and innovative concepts,
approaches or methods? Will the project develop new methodologies or
technologies? How exportable are the strategies and technologies that
will be developed by this center?
INVESTIGATORS: Are the investigators appropriately trained and well
suited to carry out this work? Is the work proposed appropriate to the
experience level of the Principal Investigator and other researchers?
Does the Principal Investigator have the appropriate management and
administrative skills?
ENVIRONMENT: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of adequate institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the
following items will be considered in the determination of scientific
merit and the priority score:
o Plans and previously demonstrated success for protein family
classification and target selection, including plans for their
applicability to the goals of the PSI Research Network
o Plans and previously demonstrated success in producing and
determining unique, non-redundant protein structures in a high-
throughput operation
o Plans and assurances that the center will carry out the work
assigned by the Steering Committee (Target selection goals #1 and #3)
and meet the production goals of the PSI Research Network
o Plans and previously demonstrated success in increasing throughput,
efficiency, and success rates and decreasing costs for producing and
determining the structures of proteins
o Plans and previously demonstrated success in developing innovative
methodologies and technologies for the production and structural
determination of proteins
o Merit of the center’s research project with a significant biomedical
theme (Target selection goal #2) and plans for accomplishing it
o Plans for producing and determining unique, non-redundant protein
structures from one or more classes of challenging proteins
o Plans and previously demonstrated success in operation of a high-
throughput structural pipeline that includes all constituent tasks
o Plans and previously demonstrated success for handling intellectual
property issues, for sharing results and materials generated by this
research, and for prompt placement of data in the public domain,
including deposition of coordinates in the Protein Data Bank and
placement of appropriate data in the PSI Network Knowledge Base
o Plans and previously demonstrated success for managing a large
research project (including plans for management of the Center
Development Fund, if this was requested in the budget).
ADDITIONAL REVIEW CONSIDERATIONS
Sharing Research Data
Applicants requesting more than $500,000 in direct costs in any year of
the proposed research must include a data sharing plan in their
application. The reasonableness of the data sharing plan or the
rationale for not sharing research data will be assessed by the
reviewers. However, reviewers will not factor the proposed data
sharing plan into the determination of scientific merit or priority
score. (http://grants.nih.gov/grants/policy/data_sharing )
BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: September 10, 2004
Application Receipt Date: October 15, 2004
Peer Review Date: February/March 2005
Council Review: May 2005
Earliest Anticipated Start Date: July 2005
AWARD CRITERIA
Criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities, including the uniqueness and contribution
of the proposed center to the overall goals of the PSI-2.
REQUIRED FEDERAL CITATIONS
SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date,
investigators submitting an NIH application seeking $500,000 or more in
direct costs in any single year are expected to include a plan for data
sharing or state why this is not possible.
http://grants.nih.gov/grants/policy/data_sharing Investigators should
seek guidance from their institutions, on issues related to
institutional policies, local IRB rules, as well as local, state and
Federal laws and regulations, including the Privacy Rule.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation,
Internet addresses (URLs) should not be used to provide information
necessary to the review because reviewers are under no obligation to
view the Internet sites. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet
site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.healthypeople.gov/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject
to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review. Awards are made under the
authorization of Sections 301 and 405 of the Public Health Service Act
as amended (42 USC 241 and 284)(cite appropriate authorizations) and
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite
relevant regulations). All awards are subject to the terms and
conditions, cost principles, and other considerations described in the
NIH Grants Policy Statement. The NIH Grants Policy Statement can be
found at http://grants.nih.gov/grants/policy/policy.htm
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.
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