STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS

RELEASE DATE:  February 11, 2002

PA NUMBER:  PA-02-060

EXPIRATION DATE:  March 15, 2005, unless reissued.

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Institute of General Medical Sciences
National Cancer Institute
National Institute on Aging
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Deafness and Communicative Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The purpose of this program announcement (PA) is to encourage basic research 
on the structures of membrane proteins at atomic resolution.  It replaces and 
updates previous program announcements (PA-99-004 and PA-95-035), which were 
issued under the same title.  

Considerable research is ongoing in the area of membrane protein structure 
and function, yet relatively few investigators have applied the techniques of 
x-ray crystallography, electron diffraction, or nuclear magnetic resonance 
(NMR) spectroscopy to study directly the structures of their proteins.  
During the past decade, approximately 30 membrane protein structures have 
been solved and each structure has been a major contribution in its area of 
science (see:  http://blanco.biomol.uci.edu/Membrane_Proteins_xtal.html).  
This progress clearly demonstrates that obtaining membrane protein structures 
is feasible.  However, during this same decade the rate of soluble protein 
structure solution has accelerated greatly and there remains a gap between 
the understanding of membrane proteins and their soluble protein counterparts.  

The Protein Structure Initiative (PSI) (see: 
http://www.nigms.nih.gov/funding/psi.html) proposes to accelerate the rate of 
protein structure solution even more.  Some of the PSI centers include 
efforts to determine membrane protein structures, and the PSI program 
announcements encourage support of technology development for high-throughput 
approaches to membrane protein structure determination (see:  
http://grants.nih.gov/grants/guide/pa-files/PA-99-116.html).  Nonetheless, 
there remains a need for a separate program initiative that focuses primarily 
on membrane proteins and the development of methods for solving their 
structures. An increase in the number of known membrane protein structures 
will contribute to an enhanced understanding of many basic phenomena 
underlying cellular functions essential to human health.

RESEARCH OBJECTIVES

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 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 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 of membrane proteins.  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, have led to new 
opportunities.  Further, the solution of crystal structures, once suitable 
crystals are obtained, has, in many cases, become sufficiently routine, that 
crystallization itself is often the more challenging undertaking.  For this 
program announcement, therefore, protein production, protein crystallization, 
and structure solution are all considered worthy aims.

The objective of this program announcement is two-fold:

1) To encourage more 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.

Examples of methods identified as needing specific attention include, but are 
not limited to:

o  Methods for over-expression of native and modified membrane proteins;

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

o  Methods for crystallization of membrane proteins and crystal manipulation 
that could facilitate data collection;

o  Methods for electron diffraction, particularly for the production of 
suitable 2D-crystals;

o  Methods for NMR analysis of membrane proteins in solution, in micelles, 
and in their native lipid environments;

o  Methods to elucidate the organization of lipid and detergent molecules 
within protein crystalline arrays (e.g., neutron diffraction).

The techniques of x-ray or electron diffraction and of NMR spectroscopy have 
been emphasized in this announcement, since they presently show the most 
promise for producing the most complete high resolution information for the 
largest number of proteins.  However, other methods that can provide atomic 
resolution information in selected cases 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.

The following are examples of the types of membrane proteins of interest to 
the participating institutes:

o  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; channels, pores, and 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; and enzymes 
involved in the biosynthesis of natural products.

o  Membrane proteins and membrane complexes of interest to the National 
Cancer Institute include those associated with the biology, diagnosis and 
treatment of cancer.  Proteins of specific interest include those membrane 
proteins whose alterations have been shown to be linked to the development 
and progression of cancer.  In addition membrane proteins that are part of 
cancer related signaling pathways are also of interest.  Of special interest 
are the proteins associated with the extracellular matrix (for example 
laminins and fibronectin).  Proteins with potential as diagnostic markers 
and/or therapeutic targets will also be of high interest.  The National 
Cancer Institute is also soliciting applications focused on the development 
of new approaches and technologies for the isolation, purification, and 
structure determination of these proteins.  Applicants strictly focused on 
technology should consider applying under the NCI Innovative Molecular 
Applications of Technology Program.  See:  
http://otir.nci.nih.gov/tech/funding.html.

o  Membrane protein systems of interest to the National Institute of 
Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have specific 
relevance to one of the following programmatic areas: muscle function and 
disease; bone and cartilage function and disease; and skin function and 
disease.  Examples of NIAMS interests are: structural aspects of membrane 
proteins in muscle disease, excitation, relaxation, force transduction, 
cellular homeostasis and metabolism, regulators of cell-cell communication 
and attachment (e.g., costameres, myotendinous and neuromuscular junctions), 
ion channels, receptors, transporters and enzymes that effect muscle function 
and hypertrophy or atrophy; and structural aspects of membrane proteins in 
skin as they are involved in the establishment of the stratum corneum 
barrier, epidermal cell-cell attachment and communication, transmembrane 
signaling and transport, and cell movement, including genetic and acquired 
diseases of skin in which the membrane protein is defective or targeted 
(which may encompass both benign and malignant hyperproliferative diseases).

o  Membrane protein systems of interest to the National Institute on Deafness 
and Communication Disorders (NIDCD) include proteins involved in the 
auditory, vestibular, olfaction, smell, voice, speech and language sensory 
systems.  Of special interest are eukaryotic protein systems including 
transport proteins, ion channels, ligand receptors, G-protein coupled 
receptors, transcription and associated factors, motor and motor associated 
proteins, growth factor receptors, and cytoskeletal structural components 
involved in the function of these sensory and neural functions.  Further, the 
NIDCD is also interested in prokaryotic membrane proteins from numerous viral 
and microbial organisms involved in otitis media.  In addition to multiple 
eukaryotic host cell receptor ligands, these prokaryotic proteins would 
include microbial specific factors such as muscin, and other potential 
proteins serving as identifiable markers for middle ear infections.

o  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: diseases of transport 
such as cystic fibrosis and peroxisomal biogenesis disorders; 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; and genetic metabolic disorders.  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 ATP 
Binding Cassette transporter superfamily or traffic ATPases in bacteria and 
yeast that serve as models for the cystic fibrosis transmembrane 
regulator (CFTR).

o  Membrane protein systems of particular interest to the National Institute 
of Environmental Health Sciences (NIEHS) include those proteins/enzymes 
involved in the response of cells to environmental toxicants.  These 
proteins/enzymes may include the components of the stress signaling pathway, 
ion channels involved in transport of xenobiotics (e.g., membrane 
transporters as PgP and MDR, MRP2, transporters and enzymes responsible for 
the uptake metabolism and clearance of environmental toxicants, targets of 
toxicant action including the Ah receptor nonclassical receptors for 
endocrine disrupting agents, and membrane bound heat shock proteins).

o  Membrane protein systems of interest to the National Institute of 
Neurological Disorders and Stroke (NINDS), the National Institute of Mental 
Health (NIMH), and the National Institute on Aging (NIA) include 
neurotransmitter and growth factor receptors, transporters, ion pumps, 
voltage- and ligand-gated ion channels, trafficking proteins, mitochondrial 
proteins, structural proteins and other proteins involved in the normal 
function and pathology of cells (neurons and glia) in the central and 
peripheral nervous system. An additional interest is in proteins involved in 
synaptic transmission and in the regulation, metabolism, and homeostasis and 
signaling in the brain during functions such as learning and memory or 
cognition, during development and aging into late-life, and in CNS disorders.

Summary

The purpose of this program announcement is to stimulate research leading to 
the solution of membrane protein structures at atomic resolution.  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 proteins associated with many of the cellular functions listed 
above is also supported by the participating Institutes.  However, this 
program announcement is intended to emphasize the need for additional 
research on structural aspects of the membrane proteins involved in 
these processes.

MECHANISM(S) OF SUPPORT 

This PA will use the NIH R01 award mechanism(s).  As an applicant, you will 
be solely responsible for planning, directing, and executing the 
proposed project.

Some research efforts may be more appropriate for the Program Project (P01) 
grant mechanism or the Integrative and Collaborative Approaches to Research 
(R24) grant mechanism.  Investigators interested in applying for P01 or R24 
grants should contact the program staff listed under inquiries to ascertain 
which Institutes may allow such applications.

A program announcement on the Structural Biology of Membrane Proteins for 
Small Business Innovation Research/Small Business Technology Transfer 
(SBIR/STTR) applications also has been issued (see:  Insert URL when published).

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups, as well as individuals with disabilities, are always 
encouraged to apply for NIH programs.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

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) 594-5938
FAX:  (301) 480-2802
Email:  preuschp@nigms.nih.gov

Jean Chin, 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)-594-2485
FAX:  (301) 480-2004
Email:  chinj@nigms.nih.gov

John C. Norvell, 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) 594-0533
FAX:  (301) 480-2004
Email:  norvellj@nigms.nih.gov

Daniel Gallahan, Ph.D.
Chief, Structural Biology and Molecular Applications Branch
Program Director, Cancer Cell Biology Branch
Division of Cancer Biology
National Cancer Institute
Room 5000, EPN
6130 Executive Blvd.
Rockville, MD  20892-7385
Telephone:  (301) 435-5226
FAX:  (301) 480-2854
Email:  dg13w@nih.gov

Bradley C. Wise, Ph.D.
Program Director, Fundamental Neuroscience
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307 MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  wiseb@nia.nih.gov

Richard W. Lymn, Ph.D.
Muscle Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5128
FAX:  (301) 480-4543
Email:  lymnr@exchange.nih.gov

Nancy L. Freeman, Ph.D.
National Institute on Deafness and Other Communication Disorders
Executive Plaza South-400C
6120 Executive Blvd, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-3458
FAX:  (301) 402-6251
Email:  nancy_freeman@NIH.gov

Salvatore Sechi, Ph.D.
Director, Proteomic Program
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd. Rm. 611
Bethesda, MD  20892-5460
Telephone:  (301) 594-8814
FAX:  (301) 480-2688
Salvatore_Sechi@nih.gov

Jose Velazquez, Ph.D.
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-21
Research Triangle Park, NC  27709
Telephone:  (919) 541-4998
FAX:  (919) 541-4937
Email:  velazqu1@niehs.nih.gov

Chiiko Asanuma, Ph.D.
Signal Transduction Program
National Institute of Mental Health
6001 Executive Boulevard, Room 7183, MSC 9641
Bethesda, MD  20892
Telephone:  (301) 443-5288
FAX:  (301) 443-4822
Email:  cs2j@nih.gov

Randall R. Stewart, Ph.D.
Program Director for Channels, Synapses and Circuits
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center, Room 2135
6001 Executive Blvd.
Bethesda, MD  20892-9523
Telephone:  (301) 496-1917
FAX:  (301) 402-1501
Email:  stewartr@ninds.nih.gov

o Direct your questions about peer review issues to:

Donald Schneider, Ph.D.
Division of Molecular and Cellular Mechanisms
Center for Scientific Review
Rockledge 2/RM 4172, MSC 7806            
Bethesda, MD  20892-7806
Telephone:  (301) 435-1727
FAX:  (301) 480-2327 
Email:  schneidd@drg.nih.gov

o Direct your questions about financial or grants management matters to:

Ms. Grace Tuanmu
Grants Administration Branch
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5520
FAX:  (301) 480-2554
Email:  tuanmug@nigms.nih.gov

Mr. William Wells       
Grants Administration Branch         
National Cancer Institute     
Executive Plaza South, Suite 243        
Bethesda, MD  20892          
Telephone:  (301) 496-8796    
Fax:  (301) 496-8601   
Email:  ww14j@nih.gov

Ms. Linda Whipp
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:  WhippL@nia.nih.gov

Ms. Nancy D. Curling
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin
Diseases 45 Center Drive, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3503
FAX:  (301) 480-5450
Email:  curlingn@exchange.nih.gov

Ms. Sara C. Stone
Chief, Grants Management Branch
National Institute of Deafness and Communication Disorders
Executive Plaza South, Room 400B
6120 Executive Boulevard, MSC-7180
Bethesda, MD20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758
Email:  stones@nidcd.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) 594-8848
FAX:  (301) 480-3504
Email:  donna_huggins@nih.gov

Mrs. Dorothy Duke
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-22
Research Triangle Park, NC  27709
Telephone:  (919) 541-2749
FAX:  (919) 541-2860
Email:  duke3@niehs.nih.gov

Ms. Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD  20892
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  diana_trunnell@nih.gov

Ms. Tina Carlisle
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 1004
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  tc48k@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email:  GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:  
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
	
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by or mailed before the 
receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA 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 application must include an Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board
	
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 your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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, you 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider 
alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below.)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

OTHER REVIEW CRITERIA:  A premise of this program announcement is that 
protein production and crystallization, not just structure solution, are 
worthy aims requiring support.  Therefore, lack of crystals that diffract to 
high resolution should not be considered a weakness of a proposal.  The 
availability of such crystals may be considered a strength.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 
 
It is not anticipated that proposals submitted in response to this PA will 
involve human subject studies.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

Applicants are reminded of the NIH policy that requires the deposition of 
atomic coordinates of solved protein structures into structural databases.  
See:  http://grants.nih.gov/grants/guide/notice-files/not99-010.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.113, 93.173, 93.242, 93.396, 93.821, 
93.846, 93.847, 93.854, 93.859, and 93.866, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.


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