MOUSE MODELS OF DIABETIC COMPLICATIONS CONSORTIUM
Release Date: October 31, 2000
RFA: DK-01-009 (This RFA has been renewed, see RFA-DK-05-011)
National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung, and Blood Institute
National Eye Institute
National Institute of Dental and Craniofacial Research
Juvenile Diabetes Foundation International
Letter of Intent Receipt Date: February 28, 2001
Application Receipt Date: March 28, 2001
PURPOSE
The intent of this initiative is to assemble a cross-disciplinary Mouse
Models of Diabetic Complications (MMDC) Consortium to develop innovative
mouse models that closely mimic the human complications of diabetes.
Complications to be examined include diabetic kidney disease, retinopathy,
neuropathy, micro- and macrovascular disease, peripheral vascular disease,
hypertension, impaired wound healing, diabetic cardiomyopathy, abnormalities
of the coagulation system, urinary tract infection, oral diseases, and
altered gastrointestinal and bladder function. The first goal of this
Consortium is to generate animal models that will be useful for studying
disease pathogenesis, prevention, and treatment. The second goal of this
Consortium is to test the role of candidate genes or chromosomal regions that
emerge from genetic studies of human diabetic complications, particularly
diabetic kidney disease and accelerated cardiovascular diseases. Each Unit
in the Consortium must contain expertise in mouse genetic engineering, organ-
specific phenotyping in the mouse, and at least one diabetic complication.
The Consortium will define standards, including gene expression profiling, to
validate each diabetic complication model for its similarity to human
disease. The Units will utilize innovative mouse genetic engineering
techniques to create diabetic mice with altered expression of potential
target-organ disease genes. The Units will derive, characterize, validate,
and use the models for various aspects of basic, developmental, or
translational research, including testing strategies for prevention, early
detection, therapy, or diagnostic imaging.
Consortium Units will have access to resources, information, technologies,
ideas, and expertise that are beyond the scope of any single research team.
As mouse models are developed and validated, NIH will provide a mechanism to
freely disseminate the mouse models and information related to them to the
scientific community.
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, Mouse Models of
Diabetic Complications Consortium, is related to the priority areas of
Diabetes and Chronic Disabling Conditions and to Chronic Renal Disease.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of
the Federal Government. Foreign institutions are not eligible.
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as principal investigators.
MECHANISM OF SUPPORT
The administrative and funding instrument to be used for this program will be
a cooperative agreement (U01), an assistance mechanism (rather than an
acquisition mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during performance
of the activity. Under the cooperative agreement, the NIH purpose is to
support and/or stimulate the recipient"s activity by involvement in and
otherwise working jointly with the award recipient in a partner role, but NIH
is not to assume direction, prime responsibility, or a dominant role in the
activity. Details of the responsibilities, relationships, and governance of
the study to be funded under cooperative agreement(s) are discussed later in
this document under the section "TERMS AND CONDITIONS OF AWARD."
This RFA is a one-time solicitation. The total project period for an
application submitted in response to this RFA may not exceed five years. The
anticipated award date is September 30, 2001.
FUNDS AVAILABLE
The NIH intends to commit approximately $4,500,000 in FY 2001 to fund up to
five to six new Mouse Engineering and Phenotyping Units and one Coordinating
and Bioinformatics Unit in response to this RFA. The Juvenile Diabetes
Foundation International intends to commit up to $500,000 to this program.
Although not participating in the RFA, NIA is interested in co-funding
applications that include components relevant to aging.
An applicant for a Mouse Engineering and Phenotyping Unit may request a
project period of up to five years and budget for direct costs of up to
$500,000 per year. Should an applicant plan to include subcontracts to other
institutions or organizations, only the direct costs of those subcontracts
will be used to tally the direct costs that apply toward the $500,000 direct
costs cap, there is no cap on total costs. An applicant for a Coordinating
and Bioinformatics Unit may request a project period of up to five years and
budget for direct costs of up to $300,000 per year. For further budget
information, see the section APPLICATION PROCEDURES. Because the nature
and scope of research proposed in response to this RFA may vary, we
anticipate that the size of awards will vary also. Although this program is
provided for in the financial plans of the NIDDK, awards pursuant to this RFA
are contingent upon the availability of funds for this purpose and the
receipt of a sufficient number of applications of outstanding scientific and
technical merit. At this time, the NIDDK has not determined whether or how
this solicitation will be continued beyond the present RFA.
RESEARCH OBJECTIVES
Background
Recognition, prevention, and treatment of diabetic complications are central
problems in both type 1 and type 2 diabetes mellitus. In the United States,
diabetes accounts for 42 percent of all new cases of end-stage renal disease,
50 percent of all non-traumatic amputations, and the majority of new
blindness in people ages 20-74. More than 60 percent of people with diabetes
are affected by neuropathy. Macrovascular complications are a major cause of
morbidity and mortality in diabetes, particularly in patients with
nephropathy. Major risk factors for macrovascular complications of diabetes
are dyslipidemia, hypertension, and cigarette smoking, the same risk factors
for cardiovascular disease. Cardiovascular disease is the leading cause of
mortality, morbidity, and disability in the United States and is
approximately four times higher among diabetic patients compared to non-
diabetics. Diabetes also markedly increases the risk of developing oral
complications such as severe periodontitis. Because diabetic nephropathy
does not occur in over half of patients with diabetes, and because there is
significant familial clustering of patients with diabetic nephropathy in the
African American and Native American communities, there may be one or more
susceptibility genes for diabetic nephropathy. Diabetics are also at risk
for developing genetic forms of hyperlipidemia such as familial
hypercholesterolemia, suggesting that there may be one or more susceptibility
genes for this problem.
Genetic technology has advanced so that it is theoretically possible to
genetically engineer mice that will develop diabetic complications analogous
to the major human complications of diabetes. Such accurate models of human
diabetic complications would be especially valuable to analyze the initiation
and progression of diabetic complications, to provide the framework for the
discovery of genes and cellular parameters that generate susceptibility or
provide resistance, to furnish targets for intervention and treatment, and to
permit testing of prevention, detection, therapeutic, and imaging strategies
in the context of a normal tissue environment. Furthermore, it is now
possible to more carefully phenotype both human patients and mouse models
using unbiased techniques such as systematic gene expression.
Several well-characterized mouse models of diabetes exist, however, these
mice models have been used mainly to study the mechanisms for developing
diabetes and the metabolic complications. In contrast, the pathogenesis of
end-organ damage has received less mechanistic attention. Studies of
complications have been largely descriptive--often reporting only histologic
changes. Time and funding constraints often do not permit an in-depth,
comprehensive analysis and characterization of diabetic complications
developed by these mice. Even fewer models are tested for their response to
treatment or prevention modalities or their suitability for testing early
detection or imaging applications. The genes that confer susceptibility to
diabetic nephropathy, accelerated atherosclerosis, or cardiovascular disease
are unknown. The possible interrelationships between different complications
(for example, neuropathy and macro- or microvascular disease) that interact
in diabetic patients have not been systematically studied in animal models.
The NIH supports many individual projects that involve the derivation or
study of mice that develop diabetes. However, at the present time, the NIH
does not support a coordinated, collaborative effort to produce highly
accurate mouse models of diabetic complications, particularly for the early
design, derivation, characterization, and validation phases of model
building. Furthermore, NIH has not ensured that the models and the data
relevant to them are readily available to the research community for further
investigation or application.
Objectives and Scope
The intent of this initiative is to assemble projects for a
cross-disciplinary, multi-institutional MMDC Consortium whose component teams
of investigators will refine or derive accurate mouse models of human
diabetes complications. The approaches used for generating, characterizing,
and validating the mice for research will reflect the blend of experience and
creativity of the Consortium component units and will be originated by these
investigators. The Consortium will validate the models for use by the
research community for a variety of investigations, including for testing
therapeutic, prevention, early detection, or imaging strategies, and assure
their availability to the research community.
It is anticipated that up to five or six Mouse Engineering and Phenotying
Units will be awarded. Each unit will consist of a cross-disciplinary team
that may reside, if appropriate, at several institutions. A separate award
will support a Coordinating and Bioinformatics Unit.
A. Interactions
The MMDC Consortium, through its component units, Steering Committee, and
other committees will:
o Define the parameters by which the diabetic complications will be validated
(gene expression profiling, pathology, anatomy and functional phenotype,
imaging, etc.), if necessary, the Consortium may acquire new human phenotypic
data (for example, by gene profiling),
o Define the complications for which appropriate models exist and select
those that should be comprehensively characterized and refined, if necessary,
o Define the complications for which no acceptable model exists and a
model(s) must be designed, derived, and comprehensively characterized,
o Define standards for phenotyping, treating, and monitoring diabetic mice
(blood sugar, insulin levels, response to glucose load, hyperinsulinemic
clamp, etc.),
o Define standards for assessing the impact of glycemic control on the
development of complications,
o Identify technological impediments to designing accurate models, and select
strategies to surmount them,
o Share technological, methodological, and phenotype information both between
component Units and with the broader research community,
o Share engineered mice between Units so mice can be phenotyped for a variety
of diabetic complications,
o Decide when a model is sufficiently characterized and validated so that the
model itself, and all available accompanying data, can be distributed to the
research community for individual investigator-initiated projects.
At each step, input will be sought from experts both within the MMDC
Consortium, within other NIH-sponsored consortia [for example, D-GAP (RFA DK-
97-007), Familial Investigation of Nephropathy of Diabetes (RFA DK-99-005),
and Mouse Metabolic Phenotyping Centers for Models of Diabetes and its
Complications (RFA DK-00-014)], and from the broader research community.
The NIH will establish the required distribution systems to disseminate the
mouse models to the research community.
During the course of the funding period, technologies will improve and the
rate of progress and scope of research under the cooperative agreement may
change. Principal Investigators, in consultation with NIH program staff,
will be expected to make necessary adjustments to accommodate the changing
research environment, to remain focused on appropriate goals, to maintain
excellent coordination with the other projects funded under this RFA, and to
incorporate new technological advances.
B. Mouse Engineering and Phenotyping Units
Each Unit will be a self-assembled group of investigators from one or more
institutions who contribute to the MMDC Consortium a unique blend of
complementary research experience. An applicant team will incorporate an
appropriate mix of expertise needed to achieve the Unit’s goals and to
contribute substantially to achieving the overall MMDC Consortium goals.
Units will be expected to focus on either one or a small number of diabetic
complications. Units do not need expertise in all areas of diabetes
complications. Each team must contain expertise in mouse genetic
engineering, organ-specific phenotyping in the mouse, and at least one
diabetic complication. Additional areas of expertise may include, but are
not limited to: mouse genetics, phenotypic, genotypic, and genomic analyses
of resulting strains, mouse or human pathology, mouse models of human
diabetic complications, small animal imaging technologies, animal husbandry,
mechanism, therapy, prevention, early detection, or diagnostic imaging
research, and the clinical properties of human diabetic complications that
inform the design of therapy, prevention, and early detection strategies.
The approaches used to generate, characterize, and validate mouse models will
reflect the blend of experience and creativity of the component
investigators. The following example is intended only to provide broad
direction and should be considered illustrative, but not restrictive. An
individual application might:
1. Propose standards for validating a particular diabetic complication. If
insufficient information is available, the Unit may propose to obtain more
human anatomic, pathologic, or gene expression information from existing
databases.
2. Review the literature for existing models and pathogenic mechanisms.
3. Propose to cross diabetic mice with transgenic mice containing organ-
specific (or complication-specific) susceptibility loci. The proposal should
discuss the clinical relevance of both the diabetic mouse model and the
diabetic complication. The genetic manipulation might include standard
transgenic knock-in or knock-out approaches, cell-specific or temporal-
specific approaches, or both. Alternatively, the diabetic manipulation might
be temporally specific.
4. Propose methods to extensively characterize the mice at various times for
both diabetes and the particular diabetic complication using physiological,
pathological, imaging, and gene-profiling methods. Mice would be treated or
partially treated with insulin to prevent malnutrition, wasting, and volume
depletion and to assess the role of glycemic control on the complication.
5. Compare the mouse phenotype with data from previous human studies.
6. Use the models to find susceptibility loci and to test therapeutic,
prevention, early detection, and imaging strategies.
Participating NIH Institutes have briefly outlined broad areas of biomedical
interest related to the goals of this RFA.
NIDDK: Produce and validate mouse models of diabetic kidney disease, urinary
tract infections, altered gastrointestinal and bladder function, and the
diabetic foot. Susceptibility loci might include, for example: fibrosis-
promoting genes (TGF-beta), cell-cycle control (p21), COX-2,
renin/angiotensin system, or glomerular podocyte genes (ureteroglobin,
nephrin).
NHLBI: Produce and validate models of macro- and micro-vessel accelerated
atherosclerosis, peripheral vascular disease, inflammation, hypertension,
impaired wound healing, diabetic cardiomyopathy, and abnormalities of the
coagulation system. Examples of susceptibility loci might include genes
regulating lipoproteins, lipoprotein receptors and associated enzymes,
chemotactic substances (e.g. MCP-1), adhesion molecules (e.g. VCAM),
hemodynamic forces-affected genes, genes affecting coagulation (PAI-1),
platelet glycoprotein receptors (IIB/IIIa), alpha2/beta1 integrins, and the
renin/angiotensin system.
NEI: Produce and validate mouse models of diabetic retinopathy.
NIDCR: Produce and validate mouse models of oral complications of diabetes,
such as periodontitis, oral mucosal infections, salivary gland dysfunctions,
and oral neuropathies.
Applicants must provide methods to maintain Unit records, establish,
standardize, document, and distribute protocols, and provide for quality
control and budgetary oversight. Each Mouse Engineering and Phenotyping Unit
will establish a database to store, organize, analyze, or visualize data
generated by individual Units to facilitate dissemination of information and
data-sharing within the Consortium. Applicants must also provide methods to
establish priorities among mouse models and to oversee the daily operation of
Units.
It is anticipated that these proposals will be quite speculative and
innovative, and applications may lack preliminary data on specific effects of
a genetic manipulation on the diabetic complication or feasibility of a
particular approach. However, applications should include sufficient
information to indicate that the applicant team has sufficient expertise with
proposed techniques and that the proposed projects are feasible.
C. Data Sharing
Restricted availability of unique research resources, upon which further
studies are dependent, can impede the advancement of research and delivery of
medical care. Sharing biomaterials, data, and software in a timely manner
has been an essential element in the rapid progress that has been made in the
genetic analyses of mammalian genomes. NIH policy requires that
investigators make unique research resources readily available for research
purposes to qualified individuals within the scientific community after
publication [NIH Grants Policy Statement
(http://grants.nih.gov/grants/policy/nihgps, 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)]. Biomaterials (engineered
mice) and other research resources that can be patented (e.g., phenotypic
screens and genetic and phenotypic data for all mouse strains) produced in
projects funded by this RFA are expected to be made available and distributed
to the broader scientific community.
The NIH is interested in ensuring that research resources developed through
this RFA become readily available to the research community for further
research, development, and application, with the expectation that sharing
will lead to products and knowledge to benefit the public. For this reason,
NIH is concerned that patents on mouse strains, phenotypic screens, and
phenotypic and genetic data for all mouse strains and other research
resources might have a chilling effect on the future development of products
and information that may improve the public health. At the same time, NIH
recognizes the rights of grantees to elect and retain title to subject
inventions developed with Federal funding under the provisions of the
Bayh-Dole Act.
All applications are expected to include the following (see the section
SPECIAL INSTRUCTIONS ):
o Proposed sharing plans to insure that mice, phenotypic screens, and genetic
and phenotypic data for all mouse strains are widely available to the
scientific community.
o A proposed plan addressing if, or how, the PI and grantee institution will
exercise their intellectual property rights regarding patentable research
resources, such as engineered mice, phenotypic screens, and phenotypic and
genetic data for all mouse strains produced in projects funded under this
RFA.
Applicants are encouraged to discuss proposals for addressing these
requirements with their institutional offices of technology transfer.
D. Coordinating and Bioinformatics Unit
The Coordinating and Bioinformatics Unit will establish and maintain an
Internet-based mechanism for rapid data and document transmission and
electronic communication among participants in the MMDC Consortium and
between the MMDC Consortium and the NIH. The Unit will also establish and
maintain a centralized and comprehensive Internet-based mouse database that
will compile important information about mouse strains developed and studied
by the MMDC. These databases and web sites will serve the needs of all Units
established by this initiative and will be an important interface between the
MMDC Consortium and the larger research community. Applicants should
address data sharing, confidentiality, and security considerations.
The Coordinating and Bioinformatics Unit will also provide travel and meeting
support for the Steering Committee and other committees of the MMDC
Consortium (see the section SPECIAL INSTRUCTIONS ).
E. Steering and Other Committees
The Principal Investigator and co-PI must be willing to be part of a Steering
Committee that will meet twice each year together with NIH program staff to
encourage exchange of information among investigators who participate in this
program. The Steering Committee may form other committees (for example,
model validation, model phenotyping, technology) that will meet once or twice
a year either in person or by telephone conference calls. A major goal of
these meetings is to facilitate progress by providing a forum for sharing
skills, ideas, technology, data, and biological reagents. At the meetings,
participants will also discuss quality assurance, bioinformatics,
coordination, and training. If voting is necessary for an action item, NIH
Program Scientists will share one vote.
TERMS AND CONDITIONS OF AWARD
The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator(s) and to the
institutional official at the time of award. These 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,
and other HHS, PHS, and NIH Grant Administration policy statements.
The administrative and funding instrument used for this program is a
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during performance
of the activity. Under the cooperative agreement, the NIH purpose is to
support and/or stimulate the recipient"s activity by involvement in and
otherwise working jointly with the award recipient in a partner role, but it
is not to assume direction, prime responsibility, or a dominant role in the
activity. Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardees for the project as
a whole, although specific tasks and activities to carry out the studies will
be shared by awardees and NIH Program Scientists.
1. Awardee Rights and Responsibilities
o The PI will have primary authority and responsibility to define objectives
and approaches and to plan, conduct, analyze, and publish results,
interpretations, and conclusions of studies conducted under the terms and
conditions of the cooperative agreement award.
o The PI will assume responsibility and accountability to the applicant
organization officials and to the NIH Institutes for the performance and
proper conduct of the research supported by the project in accordance with
the terms and conditions of the award.
o The PI and another senior investigator will serve as voting members of the
Steering Committee, will attend the Planning Meeting and two Steering
Committee meetings in the first year, and two Steering Committee meetings a
year in subsequent years.
o The PI will be responsible for accepting and implementing the goals,
priorities, procedures, protocols, and policies agreed upon by the Steering
Committee and subcommittees.
o The PI will be responsible for close coordination and cooperation with the
other components of the MMDC Consortium and with the NIH staff.
o Awardees will retain custody of, and have primary rights to, the data
developed under these awards, subject to Government rights of access
consistent with current HHS and NIH policies. Investigators conducting
biomedical research frequently develop unique research resources. The policy
of the PHS is to make available to the public the results and accomplishments
of the activities that it funds. All awardees must adhere to PHS policy for
the distribution of unique research resources produced with PHS funding that
was published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 25,
No. 23, July 12, 1996), and is available at the following Internet address:
http://grants.nih.gov/grants/guide/notice-files/not96-184.html.
o NIH reserves the right to require the transfer of appropriate mouse stocks,
related reagents, and pertinent data that are generated as the result of
participation in research supported under these awards to an eligible third
party, in order to preserve the mouse models and data about them and/or to
continue the research. Third parties supported under these awards must be
informed of this right.
o Effective conduct of the MMDC Consortium goals will require considerable
electronic communication of data and other information among the MMDC
Consortium components and between the components and the NIH. Consortium
members will be required to demonstrate that they have the ability to
transfer data accurately and effectively.
o The Coordinating and Bioinformatics Unit will coordinate the logistics of
all MMDC Consortium Steering Committee meetings, other MMDC Consortium
committee meetings, and workshops and provide an internet-based mechanism for
electronic communication among the MMDC Consortium components and the NIH.
2. NIH Staff Responsibilities
NIH Program Scientists from each participating NIH institute will have
substantial scientific-programmatic involvement during conduct of this
activity, through technical assistance, advice and coordination above and
beyond normal program stewardship for grants, as described below. The
dominant role and prime responsibility for the project as a whole resides
with the awardees, although specific tasks and activities in carrying out the
studies will be shared by awardees and the NIH.
The NIH will form an NIH MMDC Consortium External Coordinating Committee,
comprised of the NIH Program Scientists and other NIH extramural staff with
relevant scientific expertise or who manage research grant programs that
relate scientifically to the goals of the MMDC, and outside advisors picked
by the NIH. The External Coordinating Committee will meet regularly to
review the progress of the MMDC Consortium and to advise the NIH Program
Staff of scientific developments and opportunities that may enhance the
achievement of the MMDC Consortium goals.
o NIH Program Scientists from the participating institutes will be members of
the Steering Committee and, as determined by that committee, its
subcommittees.
o NIH Program Scientists will coordinate and facilitate the MMDC Consortium
programs, attend and participate as voting members in all meetings of the
MMDC Consortium Steering Committee, and provide liaison between the Steering
Committee, the MMDC Consortium, and participating institutes.
o NIH Program Scientists will help the Steering Committee develop and draft
operating policies and policies addressing recurring situations that require
coordinated action.
o NIH Program Scientists will review the scientific progress of the
individual Units, review Units for compliance with operating policies
developed by the Steering Committee, and may recommend to the funding
institutes to withhold support, suspend, or terminate an award for lack of
scientific progress or failure to adhere to policies established by the
Steering Committee.
3. Collaborative Responsibilities
Steering Committee
The NIH Program Scientists and awardees comprising the MMDC Consortium will
be responsible for forming a Steering Committee as defined below. An
arbitration system, as detailed below, will be available to resolve
disagreements among members of the Steering Committee. The Steering
Committee will be the main governing board of the MMDC Consortium. It will
develop collaborative protocols, set priorities for model derivation, define
parameters for model validation, identify technological impediments to
success and strategies to overcome them, and decide when models should be
made available to the research community for individual
investigator-initiated projects.
o The Steering Committee will be composed of the PI and a co-PI or other
senior investigator from each Mouse Engineering and Phenotyping Unit and the
Coordinating and Bioinformatics Unit, and NIH Program Scientists. The two
investigators from each Unit will share one vote. The NIH Program Scientists
will share one vote. The Steering Committee will select a chairperson who
will be someone other than an NIH staff member.
o The Steering Committee may, as it deems necessary, invite additional,
non-voting scientific advisors to meetings at which research priorities and
opportunities are discussed. The NIH reserves the right to augment the
scientific or consumer expertise of the MMDC Consortium when necessary.
o There will be two Steering Committee meetings annually, one in July in the
Washington, DC, area and the other at a time and site agreed upon by the
Steering Committee and the NIH.
o The first meeting of the MMDC Consortium will be a Planning Meeting in the
Washington, DC, area soon after grants are awarded. At the Planning Meeting,
the Steering Committee will be formed and select a chairperson from among the
members who represent the awardees. At the Planning Meeting, the Steering
Committee may: (a) draft a charter to detail policies and procedures, a
process for monitoring compliance with the policies and procedures, and a
process for recommending that the NIH Program Administrators act on evidence
of non-compliance of any Consortium component with Steering Committee
policies, (b) agree upon the terms of the charter, (c) discuss the models and
approaches that were proposed in the project applications and any relevant
new information, and set initial priorities for the models to be derived and
for new technologies to be developed, (d) discuss and set initial genotypic
and phenotypic parameters required to characterize the models and to define
their comparability to human diabetic complications, (e) discuss and set
initial standards for validating the models for further biological studies
and such uses as testing prevention or early detection strategies, or
therapies, or diagnostic imaging technologies. At the first meeting of the
Steering Committee following the Planning Meeting, an Internet-based
electronic communications mechanism will be discussed and will be implemented
by the Coordinating and Bioinformatics Unit.
o At their first meeting each year, the Steering Committee will formulate
plans for any workshops or symposia to be held.
o At the second and subsequent meetings, the Steering Committee will refine
the MMDC Consortium’s scientific objectives and characterization and
validation strategies as necessary, consistent with progress in the MMDC
Consortium components and other laboratories, and with the goals of
identifying available models with sufficient promise for further testing, or
defining those human diabetic complications for which models must be created
de novo.
o At any time during the MMDC Consortium project, the Steering Committee may
examine the characterization and validation data for models derived by the
MMDC Consortium components and decide when a model is sufficiently validated
that it may be distributed to the research community for further
investigations or applications. The NIH will provide the means to
disseminate the mice.
o The Steering Committee will plan workshops to which non-MMDC Consortium
participants will also be invited to (a) enable the MMDC Consortium to
explore scientific or technologic innovation that occurs during the course of
the project, (b) inform the research community of the progress made toward
derivation or refinement of models or their characterization and validated
uses, and (c) inform the research community of any technological advances
related to design and derivation of mouse models. The NIH Program
Scientists, the MMDC External Coordinating Committee, and other NIH staff
will provide the Steering Committee with advice on participants for the
workshops and symposia. The Coordinating and Bioinformatics Unit will manage
the logistics for these meetings.
o The Steering Committee may establish subcommittees, as it deems
appropriate, NIH Program Scientists and other NIH staff who are Steering
Committee members will serve on subcommittees as they deem appropriate.
4. Arbitration
Any disagreement that may arise on scientific/programmatic matters (within
the scope of the U01 award) between awardees and the NIH may be brought to
arbitration. An arbitration panel will be composed of three members: one
selected by the Steering Committee (with the NIH Program Scientists not
voting) or by the individual awardee in the event of an individual
disagreement, a second member selected by the NIH Program Scientists, and,
the third member selected by the two prior selected members. This special
arbitration procedure in no way affects the awardee"s right to appeal an
adverse action that is otherwise appealable in accordance with the PHS
regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part
16.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH-supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are provided indicating that inclusion
is inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a
complete copy of the updated Guidelines are available at:
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable, and b) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by
the NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for
receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
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. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
LETTER OF INTENT
Prospective applicants are asked to submit by February 28, 2001, a Letter of
Intent that includes a descriptive title of the proposed research, name,
address, and telephone number of the Principal Investigator, identities of
other key personnel and participating institutions, and the number and title
of the RFA in response to which the application may be submitted. Although a
letter of intent is not required, is not binding, and does not enter into the
review of subsequent applications, the information allows NIDDK staff to
estimate the potential review workload and to plan the review. The Letter of
Intent is to be sent to:
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Room 653 MSC 5452
Bethesda, MD 20892-5452
Bethesda, MD 20817 (for express/courier service)
Tel: (301) 594-8885
Fax: (301) 480-3505
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these awards, with the modified format that is described below.
These forms are available at most institutional offices of sponsored
research, from GrantsInfo, Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095,
Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov.
The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application. 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 2a of the face page of the application
form and the YES box must be marked.
The sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change. Please note this is in PDF format. 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 must also
be sent to:
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Room 653 MSC 5452
Bethesda, MD 20892-5452
Bethesda, MD 20817 (for express/courier service)
Tel: (301) 594-8885
Applications must be received by March 28, 2001. If an application is
received after that date, it will be returned to the applicant without
review.
The Center for Scientific Review (CSR) will not accept any application in
response to this announcement that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. The CSR will not accept any application that is essentially the
same as one already reviewed. This does not preclude the submission of a
substantial revision of an application already reviewed, but such an
application must follow the guidance in the PHS Form 398 application
instructions for the preparation of revised applications, including an
introduction addressing the previous critique.
SPECIAL INSTRUCTIONS
Applicants may apply for a Mouse Engineering and Phenotyping Unit, a
Coordinating and Bioinformatics Unit, or both. If an applicant applies for
both, separate applications must be submitted.
1. General Application Format Instructions
The form PHS 398 should be modified as follows. Biosketches and "Other
Support" pages should be included for all personnel. The number of pages
allowed for the "Research Plan" is increased from 25 to 40 pages for the
Mouse Engineering and Phenotyping Units, but remains at 25 pages for the
Coordinating and Bioinformatics Unit. Budget pages, budget justifications,
material transfer agreements, and letters from collaborators and consultants
and their biosketches are not included in this limit.
2. Applications for Mouse Engineering and Phenotyping Units
Applicants for the Mouse Engineering and Phenotyping Units should divide the
"Research Plan" into the sections indicated below.
Part 1. Infrastructure. In this part of the "Research Plan," applicants
should detail the specialized or unique facilities, fundamental
infrastructure, research expertise, and core resources and services that are
available to support the planned mouse model derivation, characterization,
and validation. If facilities at more than one institution are required,
applicants should thoroughly describe them and obtain appropriate assurances.
Methods for mouse, data, and information flow and sharing within the Unit
should be described. Applicants should discuss their barrier facilities,
requirements for importing non-SPF animals, and where the phenotyping will be
performed (behind a barrier or in a regular laboratory). The location of any
imaging equipment should be specified (i.e., is the imaging equipment in a
barrier facility?). The roles and expertise of all key personnel,
collaborators, and consultants who are associated with this part of the
application should be well documented. Applicants must also provide methods
for establishing priorities among mouse models. An internal advisory board
consisting of the Principal and co-Investigators and other important
personnel should oversee the daily operation of the Unit. Applicants should
describe how the Unit will fit into, augment, and be supported by the parent
institution and plan for designating an alternate or replacement Principal
Investigator should it become necessary.
Part 2. Model Derivation. In this part of the "Research Plan," applicants
should discuss the clinical relevance of both the diabetic mouse model and
the diabetic complication. Applicants should discuss their rationale for the
design and derivation of a new mouse model or models, or for altering and
improving an existing model or models, based on their experience with mouse
models of human disease and their knowledge of basic, translational, and
clinical diabetes research. Applicants should describe the extent to which
they plan to characterize any models they derive or refine, the methods that
they will use to characterize the models, the rationale for choices of
methods, and how generally applicable the methods are, or will be, for all
mouse diabetes and diabetes complication models. In this part as well,
applicants are expected to identify the standards they will apply to validate
a model or models, the rationale for the choices, how generally applicable
the validation standards are, or will be, for all mouse diabetes or diabetes
complication models, and, the purpose(s) for which they anticipate their
models may be used. Applicants should describe their barrier facility,
requirements to bring non-SPF animals into their institution, and the
location of the phenotyping Unit relative to the barrier. The roles and
expertise of all key personnel, collaborators, and consultants who are
associated with this part of the application should be thoroughly documented.
Part 3. Technology. In this part of the "Research Plan," applicants should
define the technologic approaches they will use, or any technology that they
propose to develop, to achieve the goals of model derivation or refinement,
characterization, and validation. The roles and expertise of all key
personnel, collaborators, and consultants who are associated with this part
of the application should be thoroughly documented.
Part 4. Interactions with Other MMDC Consortium Components and the Research
Community. In this part of the "Research Plan," applicants must include
specific plans for responding to the "Terms and Conditions of Award" section.
Applicants should state their willingness to collaborate and share data
freely with the other MMDC Consortium components and the wider research
community. Applicants must include a data sharing plan, a mouse sharing
plan, and copies of all Material Transfer Agreements and Mouse Transfer
Agreements used by all institutions involved in the application. Applicants
are encouraged to use the NIH Simple Letter of Agreement to transfer
materials, available at http://www.ott.nih.gov/policy/rt_guide_final.html#guide.
Applicants should discuss their willingness to serve on the Steering
Committee and other Consortium committees and should state their willingness
to follow the common protocols that will be developed by the Steering
Committee, particularly those that relate to setting priorities for model
development and the standards for characterization and validation.
Applicants must state their willingness to plan and attend workshops and
symposia.
Applicants should describe how their unique blend of experience can
contribute to the collective efforts of the MMDC Consortium. Applicants
should also describe how they will comply with the involvement of NIH Program
Scientists and fulfill the responsibilities of Consortium components to work
together cooperatively. Applicants should describe their experience with,
and capability for, Internet-based communication and ideas for facilitating
electronic communication and other interactions among the MMDC Consortium
components, NIH, and the general research community.
The scientific review group will evaluate the adequacy of the proposed plan
for sharing and data access. Comments on the plan and any concerns will be
presented in an administrative note in the summary statement. The adequacy
of the plan will be considered by NIH program staff and will be important in
determining whether the grant shall be awarded. The sharing plan(s) as
approved, after negotiation with the applicant when necessary, will be a
condition of the award. Evaluation of non-competing continuation
applications will include assessment of the effectiveness of research
resource release.
Applicants are reminded that the grantee institution is required to disclose
each subject invention to NIH within two months after the inventor discloses
it in writing to grantee institutional personnel responsible for patent
matters. The awarding Institute reserves the right to monitor awardee
activity in this area to ascertain if patents or patent applications on mice
identified through phenotypic screens, phenotypic screens, and phenotypic and
genotypic data for all mouse strains or other patentable subject matter are
adversely affecting the goals of this RFA.
3. Applications for the Coordinating and Bioinformatics Unit
Applicants for the Coordinating and Bioinformatics Unit should discuss
Infrastructure, Technology, and Interactions, as described above. Part 2
above should be omitted. This narrative should include, for example:
Part 1. Infrastructure. Applicants should discuss the administrative
structure of the coordinating Unit and plans for providing administrative
support for up to five meetings a year.
Part 3. Technology. Applicants should describe the Internet-based mechanism
for rapid electronic communication among participants and the NIH, the
structure of the centralized and comprehensive database, and web sites for
communication within the MMDC consortium and with the research community.
Applicants should describe issues of data validity, security, and
confidentiality.
Part 4. Interactions with other MMDC Components and the Research Community.
Applicants should discuss data sharing and willingness to participate in
common activities, committees, and workshops as outlined in Part 4 above.
Applicants must include a data sharing plan and copies of the Material
Transfer Agreements used by all institutions in the proposal.
4. Budget Instructions
Applicants who have additional funds to support ( leverage ) the application
should indicate the source of funds (institutional, R01, P01, P30, etc.) that
permit them to accomplish the project goals. Subcontract budgets should be a
separate page, and the subcontract indirect costs should be calculated and
listed in the usual place as part of the direct costs of the budget.
However, only direct costs associated with each subcontract will count toward
the direct costs cap of $500,000 on the budget for the first year.
Specific budget issues related to cooperative agreements must also be
addressed as follows.
o Applicants must budget for travel and per diem expenses for participation
in the MMDC Consortium Steering Committee, subcommittees, workshops, and
symposia. Applicants should budget for seven trips to the Bethesda, MD, area
each year.
o Applicants for the Coordinating and Bioinformatics Unit should include
travel support for 15 additional outside consultants to attend Steering and
other committees meetings and workshops in the Bethesda, MD, area each year.
REVIEW CONSIDERATIONS
General Considerations
All applications will be judged on the basis of the scientific merit of the
proposed project and the documented ability of the investigators to meet the
RESEARCH OBJECTIVES of the RFA. Although the technical merit of the proposed
protocol is important, it will not be the sole criterion for evaluation of a
study. Other factors considered to be important for review include
demonstrated expertise in mouse genetic engineering and phenotyping as
applied to the design and derivation of mouse models of human disease, a
multi-disciplinary team of collaborators, substantial interactions among
collaborating researchers, demonstration of appropriate facilities and
resources, willingness to share data and reagents freely.
Supplemental information of up to three pages will be allowed if received by
May 1, 2001. Send materials to Chief, Review Branch, at the address above.
Review Method
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIDDK. Incomplete applications will be returned to the
applicant without further consideration.
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 the NIDDK in accordance with the review criteria stated below.
As part of the initial merit review, all applications will receive a written
critique and 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, assigned a priority score, and receive a
second level review by the National Diabetes and Digestive and Kidney
Diseases Advisory Council, the National Heart, Lung, and Blood Advisory
Council, the National Eye Advisory Council, and the National Dental and
Craniofacial Research Advisory Council.
Review Criteria
Applicants are encouraged to submit and describe their own ideas about how
best to meet the goals of the cooperative study and their specific protocols,
and they are expected to address issues identified under TERMS AND
CONDITIONS OF AWARD and SPECIAL INSTRUCTIONS sections of the RFA. The
peer review group will assess the scientific merit of the applications and
related factors using the following criteria:
1. Innovation. Does the project employ novel concepts, approaches or method?
Is the project original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies? Will the approaches
advance the field of mouse or other model development?
2. Approach. Are the conceptual framework, design, methods, and analyses
adequately developed and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative
tactics? Can these approaches be used to derive mouse models of diabetic
complications in addition to those proposed? Are the parameters chosen to
characterize the model(s) sufficient and appropriate? Are these parameters
generally applicable to all mouse diabetic complication models? Are the
standards chosen to validate the model(s) for its relevance to a human
diabetic complication or for testing therapy, prevention, early detection, or
imaging appropriate and adequate?
3. Significance. Do the model or models proposed for derivation/
characterization/validation address an important need for the diabetic
complication research community? What is the immediacy of the research
opportunity? Over the project period, is there potential for the group to
develop models other than those specified in the application?
4. Investigators. Are the principal investigator and his/her collaborators
appropriately trained and well suited to carry out this work? To what extent
do these investigators have the necessary complementary skills? Have
collaborations been established or consultants identified to provide the
appropriate depth and breadth of scientific expertise required for the
project? Will this team of investigators contribute unique skills to the
overall Consortium?
5. Environment. Are the facilities for mouse maintenance and
experimentation appropriate to support the endeavor? 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 and incorporate the best use of collaborative
arrangements? Is there evidence of institutional support? If advanced
imaging techniques are proposed, is the instrument located behind an animal
barrier?
Additional Considerations
6. Interactions. Are there adequate plans for effective interaction and
coordination among Consortium components and the NIH? Are the proposed plans
to share data and mice adequate? Do the investigators state their willingness
to collaborate extensively and share information fully? Are the Material
Transfer Agreements and Mouse Transfer Agreements straightforward? Do the
investigators state their willingness to abide by the priorities and policies
agreed upon by the Steering Committee? Have the applicants proposed sound
strategies for communication among themselves, with the other MMDC
components, and with the NIH?
7. Budget. Assess the appropriateness of the proposed budget and duration
in relation to the proposed research. Does the budget for fundamental
infrastructure, model development, characterization and validation, and
technology development indicate that the applicants understand the
requirements of managing this sort of model-building enterprise?
8. Coordinating and Bioinformatics Unit. Does the Unit employ novel concepts,
approaches or methods? Are the principal investigator and collaborators
appropriately trained and well suited to provide support for multiple
investigative teams and to design and implement internet-based Web sites and
databases? Are the computer facilities (hardware, software, and personnel)
sufficient to support the endeavor? Are there adequate plans for providing
meeting support, Internet-based communication, databases, and web sites for
use by the MMDC Consortium? Have the applicants addressed data sharing
policies, confidentiality issues, and security considerations? Are there
adequate plans for open access to these databases and web sites by the
general research community?
AWARD CRITERIA
The intent of this RFA is to enable the NIDDK to assemble a Consortium of
highly qualified Units of investigators whose complementary scientific skills
and expertise will enable them to achieve the goal of deriving validated
mouse models that are analogous to human diabetic complications. The NIDDK
will choose Units for the Consortium that will collectively provide the most
creative approaches to mouse model design, and have a range of research
focus, experience, technology, and resources to ensure that a range of models
of diabetic complications are rapidly derived and validated.
Applications recommended by the NIH Advisory Councils will be considered for
award based upon (a) scientific and technical merit as determined by peer
review, (b) the importance of the proposed models for research in diabetic
complications, (c) the degree of originality and innovation in model design,
(d) the creativity of the approaches and technologies for model derivation,
characterization, and validation, (e) the likelihood for substantial
contribution by the applicants to a successful collaborative MMDC, (f) the
evidence for willingness to work cooperatively, (g) the quality and
availability of animal research infrastructure and resources, (h) program
balance, including, in this instance, sufficient compatibility of features to
make a successful collaborative program a reasonable likelihood, and (i) the
availability of funds.
Schedule
Public Information Meeting: December 2000
Letter of Intent Receipt Date: February 28, 2001
Application Receipt Date: March 28, 2001
Peer Review Date: June-August 2001
Council Review: September 2001
Earliest Anticipated Start Date: September 30, 2001
INQUIRIES
A public information meeting will be held in December 2000 in Bethesda,
Maryland. The date and time of this meeting, answers to frequently asked
questions, and other updates about this RFA will be posted on the NIDDK Web
site (or http://www.niddk.nih.gov/fund/crfo/highlights.htm) as they are
developed. Applicants are highly encouraged to visit this Web site regularly
in the course of preparing applications. Potential applicants are encouraged
to subscribe to the MMDC Discussion List at list.nih.gov/archives/mmdc-l.html
. These sites will contain the most current information available.
Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcome. Direct inquiries regarding programmatic issues that are not
addressed at the website to:
Robert A. Star, M.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
31 Center Drive, Room 9A35
Bethesda, MD 20892-2560
Tel: (301) 594-7717
Fax: (301) 496-2830
E-mail: Robert_Star@nih.gov
Momtaz Wassef, Ph.D.
Atherosclerosis Research Group
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge 2, Room 10193Bethesda, MD 20892-7956
Tel: (301) 435-0550
Fax:(301) 480-2858
E-mail: Wassefm@NIH.gov
Nancy L. Nadon, Ph.D.
Head, Office of Biological Resources and Resource Development
National Institute on Aging
7201 Wisconsin Ave./ GW 2C231
Bethesda, MD 20892
Tel: (301) 496-6402
Fax: (301) 402-0010
E-mail: nadonn@exmur.nia.nih.gov
Dennis F. Mangan, Ph.D.
Infectious Diseases and Immunity Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-32F
Bethesda, MD 20892-6402
Tel: (301) 594-2421
Fax: (301) 480-8318
E-mail: Dennis.Mangan@nih.gov
Direct inquiries regarding fiscal matters to:
Teresa Farris
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 630 MSC 5456
Bethesda, MD 20892-5456
Tel: (301) 594-7682
Fax: (301) 480-3504
E-mail: FarrisT@extra.niddk.nih.gov
Ms. Jane R. Davis
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Rockledge 2, Room 7174
Bethesda, MD 20892-7926
Tel: (301) 435-0149?
Fax: (301) 480-3310
E-mail: Davisj@NIH.Gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.121, 93.837, 93.847, 93.848, and 93.849. Awards are made under
authorization of the Public Health Service Act, Title IV, Part A (Public Law
78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts
74 and 92. This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.
The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-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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