Full Text PA-97-090
 
THREE-DIMENSIONAL STRUCTURES OF IMMUNOLOGICAL PROTEINS
 
NIH GUIDE, Volume 26, Number 26, August 8, 1997
 
PA NUMBER:  PA-97-090
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications for research on the three-dimensional structural
properties of proteins involved in initiating and regulating immune
responses in human and animal systems. The structural elucidation of
protein complexes and development of structural analogs that enhance,
inhibit or change the function of native proteins for therapeutic
applications are also of interest. Increased knowledge of
immunological proteins obtained from such structural studies is
important for understanding regulation of the immune system and for
the development of effective immunotherapeutic agents.
 
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.  This Program
Announcement (PA), "THREE-DIMENSIONAL STRUCTURES OF IMMUNOLOGICAL
PROTEINS", is related to the priority area of Immunization and
Infectious Diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY
 
Applications may be submitted by 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.  Domestic and foreign
institutions are eligible to apply for R01 grants.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) awards (R29). Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
Traditional research project grant(R01)and FIRST (R29) applications
may be submitted in response to this program announcement.
Applications for R01 grants may request up to five years of support;
applications for R29 grants must request five years of support.
Applicants for the FIRST award must comply with the NIH Guidelines
for FIRST awards and the Just-in-Time procedures announced in the NIH
Guide, Vol. 25, No. 10, March 29, 1996.  Responsibility for the
planning, direction, and execution of the proposed research for all
applicable mechanisms of support will be solely that of the
applicant.
 
RESEARCH OBJECTIVES
 
Background
 
Detailed structural analyses of antibody:antigen and peptide:MHC
complexes and, more recently, the T cell antigen receptor, have
provided information at the three-dimensional level that is essential
for understanding the rules of ligand:receptor associations and
specific sites of protein:protein interactions for these fundamental
components of the immune system. Many additional immunologically
relevant proteins have not yet been defined at the three-dimensional
level, and such information would contribute greatly to basic
understanding of immune reactions and to the rational design and
effective utilization of therapeutic agents that enhance or inhibit
immune responses. Although genetic mutational or biochemical studies
can provide useful information, biophysical approaches, such as X-ray
crystallography or nuclear magnetic resonance (NMR) spectroscopy,
provide direct and more definitive descriptions of important
structural domains. Detailed knowledge of molecular topography and
contact sites that are important for functional activation can,
therefore, form the basis for understanding fundamental concepts in
immunoregulation and identify new targets for immunotherapy.
 
Three-dimensional structural studies may confirm protein structures
postulated from less direct experimental approaches, or may provide
surprising and highly instructive data that are relevant for protein
function. In addition to work on antibodies, MHC and the T cell
antigen receptor, some examples of the importance of X-ray
crystallographic or NMR data include the development of HIV-protease
inhibitors and understanding the role of invariant chain in MHC class
II antigen presentation. In addition, structural analysis of protein
dimerization mediated by the immunosuppressive drug, rapamycin, has
spurred efforts to design structure-based strategies for regulating
intracellular signal transduction pathways and transcription factor
activation.
 
Knowledge of three-dimensional structures may also engender novel
hypotheses that are amenable to experimental testing to provide a
more comprehensive understanding of immune mechanisms. Furthermore,
the biophysical data obtained from three-dimensional studies may form
the basis for construction of peptidomimetic analogues of
immunologically relevant proteins to provide more stable and
effective therapeutic drugs.
 
Research Objectives and Scope
 
The purpose of this PA is to support research on three-dimensional
structures of immunologically relevant proteins and protein
complexes. It is NOT intended to support indirect structure:function
studies that rely solely on genetic or biochemical techniques.
Research areas of interest include, but are not limited to,
structural studies on:
 
o soluble immune mediators, such as antibodies, cytokines and
chemokines, and their receptors;
 
o leukocyte membrane adhesion or signaling receptors and their
ligands;
 
o signal transduction molecules;
 
o transcription factors involved in leukocyte activation or
downregulation;
 
o structural analogues of immunological proteins that enhance,
inhibit, or introduce a novel function for therapeutic application;
and
 
o novel technologies to facilitate three-dimensional structural
analysis.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority group
and their subpopulations 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 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 1993 (Section 4928 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 the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.
Investigators may obtain copies from these sources or from the
program staff listed under INQUIRIES. Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95) and will be accepted on the standard application
deadlines as indicated on the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Division of Extramural Outreach and Information,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
asknih@odrockm1.nih.gov. For purposes of identification and
processing, item 2 on the face page of the application must be marked
"YES".  The PA number and the PA title, "THREE-DIMENSIONAL STRUCTURES
OF IMMUNOLOGICAL PROTEINS" must be typed in section 2.
 
The completed, signed original and five legible, single-sided copies
of the application must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
 
FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.
 
Applicants from institutions that have a General Clinical Research
Centers (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Applications will be assigned on the basis of established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants. Incomplete
applications will be returned to the applicant without further
consideration.
 
Applications will be reviewed for scientific and technical merit by
study sections of the Division of Research Grants, NIH, in accordance
with the standard NIH peer review procedures. 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 appropriate national advisory
council.
 
Review Criteria
 
The five criteria to be used in the evaluation of grant applications
are listed below.  To put those criteria in context, the following
information is contained in instructions to the peer reviewers.
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques 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 by the reviewers 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 a 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.
 
1.  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?
 
2.  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?
 
3.  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?
 
4.  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)?
 
5.  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?
 
The initial 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
 
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance, and availability of
funds.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic issues may be directed to:
 
Helen Quill, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A22
Bethesda, MD 20892-7640
Telephone: (301) 496-7551
Fax:  (301) 402-2571
EMAIL:  hq1t@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Lesia Norwood
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B27
6003 Executive Blvd.
Bethesda, MD 20892-7610
Telephone: (301) 496-7075
Fax:  (301) 480-3780
Email:  ln5t@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citations are No. 93.855 -
Immunology, Allergy, and Transplantation Research and No. 93.366 -
Aging Research.  Awards will be administered under PHS grants
policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems 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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