Full Text PA-95-035


NIH GUIDE, Volume 24, Number 7, February 24, 1995

PA NUMBER:  PA-95-035

P.T. 34

  Proteins and Macromolecules 
  Membrane Structure/Function 

National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases


The purpose of this program announcement (PA) is to encourage basic
research on the structures of membrane proteins at (or near) atomic
resolution.  Considerable research is on-going in the area of
membrane protein structure and function, particularly with respect to
sequences, topology, and the effects of mutations; however, much of
this work is somewhat speculative in that the interpretations depend
upon the very limited number of structures that have actually been
solved by direct biophysical measurements.  An increase in the number
of known membrane protein structures will contribute to an enhanced
understanding of many basic phenomena underlying cellular function.


Applications may be submitted by foreign and 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 for First Independent Research
Support and Transition (FIRST) (R29) awards and program project (P01)
grants.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.


Support of this program will be through the individual research
project grant (R01), program project grant (P01), and FIRST award
(R29).  Potential applicants are strongly urged to contact the
program staff listed under INQUIRIES for guidance in the areas
appropriate for program project grant applications and the
preparation of the application itself.

Investigators holding active R01, P01, or MERIT (R37) grants to study
membrane associated processes and who are not currently supported for
work on high resolution structural studies of the relevant membrane
associated proteins may wish to consider applying for competing
supplemental awards (S01).


Membrane proteins play a crucial role in many cellular and
physiological processes.  They are essential mediators of material
and information transfer between cells and their environment, between
compartments within cells, and between compartments comprising the
organ systems.  Functionally normal membrane proteins are vital to
health and specific defects are associated with many known disease
states.  Membrane proteins are the targets of a large number of
pharmacologically and toxicologically active substances and are
responsible, in part, for their uptake, metabolism, and clearance.

Despite the importance of membrane associated proteins, the knowledge
of their high resolution structures and mechanisms of action has
lagged far behind the knowledge of these properties of proteins in
general.  This has resulted from the difficulty of obtaining x-ray
diffraction quality crystals for the membrane-embedded domains of
these proteins and the difficulty of applying well developed solution
NMR methods to the study of most membrane proteins.  These
difficulties have led to a reluctance of many investigators to pursue
high resolution structural studies.  However, in the recent past,
advances in methods for crystallization and analysis of proteins by
x-ray and electron diffraction methods, and improvements in NMR
methods, particularly solid-state NMR, have led to new opportunities.
The objective of this program announcement is two-fold:

1) To encourage investigators with interests in membrane associated
systems to pursue high resolution structural studies making use of
these recently developed technologies; and

2) To encourage additional research to further develop methods for
studying the structure of membrane proteins at atomic resolution.
Areas identified as needing specific attention include:

o  Improved methods for over-expression of native and modified
membrane proteins,

o  Improved methods for isolation, purification, and stabilization of
membrane proteins, including the development of new detergents and
non-detergent solubilization agents,

o  Basic research on the physical chemistry of membrane protein
crystallization and the development of new methods for
crystallization and crystal manipulation that could facilitate data

o  Further development of methods for electron diffraction,
particularly for the production of suitable 2D-crystals,

o  Further development of NMR methods for examining proteins in their
native lipid environments.

The techniques of x-ray or electron diffraction and of NMR
spectroscopy have been emphasized in this announcement, since it is
felt that they show the most promise for producing complete high
resolution information for the largest number of proteins.  However,
funds are also available for research using other methods that can
provide atomic resolution information in selected cases.  Methods
that can elucidate the organization of lipid and detergent molecules
within protein crystalline arrays (e.g., neutron diffraction) are
also of interest.

It is expected that many of the projects will be collaborative
efforts between biochemists and molecular biologists with expertise
in the isolation and characterization of membrane-bound proteins and
biophysicists with expertise in x-ray crystallography, NMR, and other
structural methods.  A major aim of this program announcement is to
stimulate such collaborations.

Membrane protein systems of particular interest to the National
Institute of General Medical Sciences (NIGMS) include:  energy
transducing membranes of mitochondria, chloroplasts, and bacterial
cell membranes involved in electron transport and ATP synthesis;
transporters of ions, substrates, and macromolecules between
intracellular compartments and between the cell and its environment;
enzymes in the synthesis and metabolism of lipids,
membrane-associated and secreted proteins, and glycoconjugates;
cytoskeletal proteins, including those required for intracellular
vesicle transport, cell motility, and cell division; regulators of
cell-cell communication, differentiation, and growth; receptors
relevant to cell cycle regulation, mechanisms of anesthetic action,
and trauma and burn physiology; transporters and enzymes responsible
for the uptake, metabolism, and clearance of drugs, or in other ways
affecting the bioavailability, pharmacokinetics, or action of drugs;
targets of drug action and toxicity, including targets of naturally
occurring toxins and venoms; enzymes involved in the biosynthesis of
natural products.

Membrane protein systems of particular interest to the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
should have specific relevance to one of the following programmatic
areas: cystic fibrosis; carbohydrate metabolism and its hormonal
control; diabetes mellitus; hormone receptors and signal
transduction; endocrine disorders; normal and abnormal processes of
lipid, protein, amino acid, urea, pyrimidine, metal ion and steroid
metabolism; genetic metabolic disorders; diseases of peroxisomal
metabolism; diseases of transport; diseases of amino acid metabolism.
Proteins should be of mammalian origin.  Studies on proteins of
prokaryotic or lower eukaryotic origin should be proposed as models
for mammalian systems.  An example of this is the ABC transporter
superfamily or traffic ATPases in bacteria and yeast that serve as
models for the cystic fibrosis transmembrane regulator (CFTR).

The above listings are not meant to be exclusive.  Structural
information obtained for any membrane protein will contribute to
understanding the general principles that underlie all membrane
protein structure and function.  Research on the non-membrane
embedded proteins associated with many of the cellular functions
listed above is also supported by NIGMS and NIDDK; however, this
program announcement is intended to emphasize the need for additional
research on structural aspects of the membrane-embedded proteins
involved in these processes.


Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone (301) 435-0714.

The title and number of the program announcement must be typed in
Section 2a on the face page of the application (i.e., "Structural
Biology of Membrane Proteins," PA-95-035.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

The completed original application and five legible copies must be
sent or delivered to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express mail)


Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by study sections of the Division of Research
Grants, NIH (or, for P01s, by review group of the NIGMS or NIDDK), in
accordance with the standard NIH peer review procedures.  Following
scientific-technical review, the applications will receive a
second-level review by the appropriate national advisory council.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  for R01 applications submitted by foreign organizations:
availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries which are not readily
available in the United States or which provide augmentation of
existing United States resources.

The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.


Applications will compete for available funds with all other approved
applications assigned to that Institute or Center.  The following
will be considered in making funding decisions:

o  quality of the proposed project as determined by peer review;
o  availability of funds;
o  program priority of research in the area of the program
announcement and other areas of Institute or Center interest.


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

Direct inquiries regarding programmatic issues to:

Peter C. Preusch, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-1832
FAX:  (301) 480-2802
Email:  PREUSCHP@gm1.nigms.nih.gov

James C. Cassatt, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0828
FAX:  (301) 480-2004
Email:  CASSATTJ@gm1.nigms.nih.gov

Eliezar Dawidowicz, Ph.D.
Metabolism and Structural Biology Research Program
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6200
Telephone:  (301) 594-8811
FAX:  (301) 480-3503
Email:  LENNYD@dvsgate.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Ruth Monaghan
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5135
FAX:  (301) 594-2554
Email:  MONAGHAR@gm1.nigms.nih.gov

Ms. Donna A. Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8843
FAX:  (301) 480-3504


This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.3821, 93.847, and 93.859.  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 285c-8
and 285k) 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 recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.
This is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.


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