PROTEIN STRUCTURE AND FUNCTION IN AGING & LATE-LIFE DISEASE

Release Date:  April 14, 1999

RFA:  AG-99-005

P.T.

National Institute on Aging

Letter of Intent Receipt Date:  April 30, 1999
Application Receipt Date:  June 23, 1999

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute on Aging (NIA) invites applications for research project
grants (R01) to support basic research on protein structure, function, and
integrity during the aging process and in late-life disease.  The goal of this
RFA is to solicit applications that will examine, over the life-course, certain
aspects of protein and peptide integrity that may change with age.

Proteins are responsible in part for maintaining functional stability and
homeostasis of cells and tissues.  During aging there are many opportunities for
appropriately transcribed peptides and proteins to become structurally altered. 
Accumulation of altered proteins may be correlated with a loss of function or,
in some cases, a gain of inappropriate or toxic function. Therefore, it is
critical to identify the specific alterations of proteins occurring during aging
and in disease processes, and to define the role these alterations play in age-
related and disease-related pathologies.

The ability of a protein to perform its function in the cell depends in part upon
its ability to assume and retain its proper functional conformation.  The proper
conformation is achieved by regulated folding during synthesis, aided by
chaperone proteins.  Mutations and other changes that divert proteins from their
normal folding pathways or that destabilize their native state may underlie
several human diseases.  For example, alterations of the thermodynamic stability
in folding of the native state and critical folding intermediates may prevent
folding into a functional conformation on a biological scale.  Cellular quality
control machinery must then recognize misfolded and/or partially folded products
and either refold them or mark them for recycling.  Off-pathway traps can be
caused by aggregation, mis-targeting into an inappropriate cellular location, or
proteolysis.  Proteins and peptides that are aggregated (for example, into
amyloid plaques) or cross-linked are often resistant to degradation.  The
formation of these deposits, rather than the lack of native protein, may be
responsible for, or contribute significantly to, cellular pathology. 
Accumulation of aggregated proteins thus may play an important role in the aging
process and in age-related diseases.

A multi-disciplinary approach to the study of protein structure and integrity of
function in aging and age-related diseases is envisioned.  By using a combined
approach and techniques from physics, biophysics, chemistry, biochemistry and
biology it should be possible to accelerate the rate of research progress to
yield a greater in-depth understanding of the molecular changes in proteins that
can take place in aging and in age-related diseases.  The goal, ultimately, would
be to intervene in these age-related diseases and processes.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000", a PHS-led national
activity for setting priority areas. Each NIH RFA addresses one or more of 22
Health Promotion and Disease Prevention priority areas identified.  These areas
can be found via the www at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals, and
laboratories, units of state and local governments, and eligible agencies of the
Federal government.  Applications from domestic institutions may include
international components if the collaborative efforts between domestic and
foreign investigators strengthen the research proposal.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to apply as
principal investigators.

MECHANISM OF SUPPORT

This RFA will use the individual research project grant (R01) mechanism. 
However, specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The
modular grant concept establishes specific modules in which direct costs may be
requested as well as a maximum level for requested budgets. Only limited
budgetary information is required under this approach. The just-in-time concept
allows applicants to submit certain information only when there is a possibility
for an award. It is anticipated that these changes will reduce the administrative
burden for the applicants, reviewers and Institute staff. Complete and detailed
instructions and information on Modular Grants can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.

Applications will request direct costs in $25,000 modules, up to a total direct
cost request of $250,000 per year. A typical modular grant application will
request the same number of modules in each year.

Application budgets will be simplified.  Detailed categorical budget information
will not be submitted with the application; budget form pages of the application
kits will not be used.  Instead, total direct costs requested for each year will
be presented.  Information, in narrative form, will be provided only for
Personnel and, when applicable, for Consortium/Contractual Costs.  See section
on application instructions below.

Additional narrative budget justification will be required in the application
only if there is a variation in the number of modules requested.

There will be no routine escalation for future years.  In determining the total
for each budget year, applicants should first consider the direct cost of the
entire project period. Well-justified modular increments or decrements in the
total direct costs for any year of the project that reflect substantial changes
in expected future activities may be requested.  For example, purchase of major
equipment in the first year may justify a higher overall budget in the first, but
not in succeeding years.

Other Support pages of the PHS 398 will not be submitted with the application.

Information on research projects ongoing or completed during the last three years
of the principal investigator and key personnel will be provided as part of the
"Biographical Sketch."  This information will include the specific aims, overall
goals and responsibilities and should include Federal and non-Federal support. 
This information will be used by reviewers in the assessment of each individuals
qualifications for a specific role in the proposed project.

Following peer review, information about Other Research Support will be requested
by NIH from the applicant for applications being considered for award.

Additional budget information will be requested only under special circumstances.

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  This RFA is a one-time solicitation. 
Future unsolicited competing continuation applications will compete with all
investigator-initiated applications and will be reviewed according to the usual
peer review procedures.

This research topic area also might be addressed using multidisciplinary
approaches benefiting from some level of formalized interaction to facilitate the
exchange of data, materials and ideas.  Thus, the submission of linked
investigator-initiated interactive research project grants (IRPG) in response to
this RFA is encouraged, as appropriate.  Guidelines to aid in the development and
submission of an IRPG are available from NIA staff or in electronic form at
http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.

Because each research project of an IRPG is an independent application, like the
typical R01, each project must stand on its own scientifically.  The
collaboration may involve limited shared resources and a modest amount of support
for core functions may be requested at the time of submission by only one of the
entities.  Thus, for some scientifically based collaborative efforts, the
exchange of data, materials, and ideas is more important than extensive, shared,
physical resources or central oversight as in a program project grant
application. However as described below, the additional cost of the core together
with the cost of the research component, whether as modules or actual cost
estimates must not exceed the upper limit of $500,000 (total cost).

The total project period for an application submitted in response to the present
RFA may not exceed four years.  The anticipated award date is March 1, 2000.

FUNDS AVAILABLE

It is estimated that as much as $2,000,000 will be available to support from four
to six new research awards.  Awards issued under this RFA are contingent upon the
receipt of highly meritorious applications and availability of funds for this
purpose.  For the first year applicants may request a maximum of five hundred
thousand dollars (total cost).  Budgets for all subsequent years should be
constructed so that the total direct costs are less than or equal to the
inflation-adjusted first year cost, or where proposed costs exceed the inflation-
adjusted prior year cost are rigorously justified.

RESEARCH OBJECTIVES

Background

It is important to know more about how proteins fold under þnativeþ conditions
as well as under abnormal conditions, and how folding is affected during aging
and by disease.  It is critical to know the effects of mutations on structure and
folding near critical regions in a protein versus polymorphisms dispersed along
the protein backbone, but having little or no apparent effect on the function of
a protein.  Membrane-spanning and membrane-associated proteins present particular
challenges.  It is also important to understand more precisely how chaperone
proteins are involved in the initial protein folding process or in the re-folding
of malformed proteins.  Likewise, the microenvironment, including pH, the
presence/absence of certain ions, availability of co-factors, and the extent of
post-translational modification in both the extracellular and intracellular
compartments may influence the process of folding or of subsequent aggregation.
The resultant changes can be simple or complex, i.e., related to changes in
expression (simple stoichiometry) or to inappropriate intermolecular
interactions.  Ultimately, such alterations could have an effect on protein
stability and function.  The role of protein degradation and ubiquitination of
incorrectly folded, non-functional proteins and aggregates is also of interest.

With respect to this announcement, a more complete understanding of all of the
foregoing elements is needed in reference to aging and, especially, in regard to
diseases with an onset late in life.  For example, it will be important to know
more about factors such as tissue concentrations of glucose and hormones that
increase, decrease or otherwise influence the rate and extent of post-
translational modifications of proteins.  How do age and cell type influence the
rates of synthesis and folding, and degradation of proteins? Stemming from those
considerations, what are the physiological and functional consequences of the
physical changes (to secondary and higher order conformations) of a proteinþs
structure? These could range from specific effects on a protein's original
function to global alterations in cellular metabolism (e.g., the initiation of
apoptotic programs).

Effective interventions for some diseases of aging will likely require a more
complete understanding of the structure of proteins and peptides that change in
conformation with age, resulting in cellular dysfunction.  To that end an
interdisciplinary approach is warranted.  For example, the structural chemist and
the biologist may need to collaborate with the biophysicist.  Such collaborations
in the context of linked R01s, especially, may best facilitate the development
of new approaches to observe or monitor aspects of protein folding.  In this way
the field should gain insights on: approaches for obtaining structural maps of
membrane and cytosolic proteins involved in disease; new imaging techniques as
probes of macromolecular interactions; and molecular modeling and therapeutic
approaches for the prevention of deposition and the removal of abnormally folded
proteins.  Such research may lead to an ability to predict, at the molecular
level, associations between proteins, and to prevent or reverse the pathogenic
alterations that lead to age-related disease.

The research objectives for the types of research and experimental approaches
that are being sought by this RFA may be either narrowly focused from the
perspective of a single discipline or broadly interdisciplinary.  Examples of
some research topics are listed below.  Such examples are intended to be
illustrative, and not restrictive or prescriptive.

o  Studies which assess changes in post-transcriptional events (such as assembly,
folding, and trafficking) and functioning of proteins (cytosolic as well as
membrane-spanning and membrane-associated) with age and age-associated diseases,
specifically in the processes that fail with age.

o  Structural studies of proteins focused on the coordinated contributions of
chaperones, repair processes, degradation and non-enzymatic reactions with
respect to a particular aging process.

o  Development of new approaches to observe or monitor aspects of protein folding
relevant to issues in aging.

o  Development of novel interventions designed to interrupt or reverse
aggregation or cross-linking of proteins that accumulate with age.

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 is provided 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

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. However, the scientific goals of this RFA are focused on
aging.  In describing the plan to recruit human subjects, investigators may cite
a focus on aging as the justification for why will be excluded.  In this regard
applicants may use Justification 1, the research topic to be studied is
irrelevant to children, from the policy announcement.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 30, 1999, a letter of intent
that includes a descriptive title of the proposed research, the name, address,
and telephone number of the Principal Investigator, the 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 a
subsequent application, the information that it contains allows NIA staff to
estimate the potential review workload and avoid conflict of interest in the
review.

The letter of intent is to be sent to:

D. Stephen Snyder, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Room 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  SnyderD@exmur.nia.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  Applications kits are available at most institutional offices
of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
GrantsInfo@nih.gov.  Applications are also available on the World Wide Web at
http://grants.nih.gov/grants/funding/phs398/phs398.html.

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 2 of the face page of the application form and the
YES box must be marked.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period.  Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At
the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project.  No individual salary information should be
provided.

For Consortium/Contractual costs, provide an estimate of total costs (direct plus
facilities and administrative) for each year, each rounded to the nearest $1,000.
List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project.  Indicate whether the collaborating institution is foreign or
domestic.  The total cost for a consortium/ contractual arrangement is included
in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team.  A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for each
person.  A sample biographical sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page;
- List current position(s) and then previous positions;
- List selected peer-reviewed publications, with full citations;
- Provide information, including overall goals and responsibilities, on research
projects ongoing or completed during the last three years.

o  CHECKLIST - This page should be completed and submitted with the application.
If the F&A rate agreement has been established, indicate the type of agreement
and the date. It is important to identify all exclusions that were used in the
calculation of the F&A costs for the initial budget period and all future budget
years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE
TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

Submit a signed, original of the application, including the Checklist, and three
signed photocopies of the application in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, SUITE 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, send two additional copies of the application to:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212
Bethesda, MD  20892-9205

It is important to send these copies at the same time as the original and three
copies are sent to the Center for Scientific Review.

Applications must be received by June 23, 1999.  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
RFA 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 substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR, and for
responsiveness by the NIA.  Incomplete applications will be returned to the
applicant without further consideration.  To be considered responsive to this
solicitation an application must include a statement summarizing the specific
age-relatedness of the proposed investigation.  That statement should be placed
within the "background and significance" section of the proposal.  If the
application is not responsive to the RFA, CSR staff may contact the applicant to
determine whether to return the application to the applicant or submit it for
review in competition with unsolicited applications at the next review cycle. 
If one (or more) component(s) of a set of linked IRPG R01s is considered
unresponsive to the RFA only the application deemed responsive will be evaluated.

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 NIA in accordance with the review criteria stated below.  As part of the
initial merit review, all applications will receive a written critique and may
undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level review by the
National Advisory Council on Aging.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments, reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

o  Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

o  Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

o  Innovation:  Does the project employ novel concepts, approaches or method? Are
the aims original and innovative?  Does the project challenge existing paradigms
or develop new methodologies or technologies?

o  Investigator:  Is the investigator 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 (if any)?

o  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 institutional support?

Where appropriate, the initial review group will look for evidence of
interdisciplinary collaboration. The review group will also examine: the
appropriateness of proposed project budget and duration; the adequacy of plans
to include both genders and minorities and their subgroups as appropriate for the
scientific goals of the research, and plans for the recruitment and retention of
subjects; the provisions for the protection of human and animal subjects; and the
safety of the research environment.

AWARD CRITERIA

Awards will be made on the basis of scientific and technical merit as determined
by peer review and reflected in the priority score or percentile, the
availability of funds, and programmatic priorities will be used to make award
decisions.

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic (scientific) issues to:

For applications with a primary emphasis on the biology of aging contact:

Pamela Starke-Reed, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  StarkeP@exmur.nia.nih.gov

For applications with a primary emphasis on the neuroscience of aging contact:

D. Stephen Snyder, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Ave., MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  SnyderD@exmur.nia.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Crystal Ferguson
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  FergusoC@exmur.nia.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.866.  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 PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74.  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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