GENETIC ASPECTS OF TUBERCULOSIS IN THE LUNG

Release Date:  September 5, 2000

RFA:  HL-00-014

National Heart, Lung, and Blood Institute
 http://www.nhlbi.nih.gov
National Institute of Allergy and Infectious Diseases
 http://www.niaid.nih.gov

Letter of Intent Receipt Date:  November 1, 2000
Application Receipt Date:       January 17, 2001

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS (these apply to the 
R01 grants).  THE FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD 
APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN 
RESPONSE TO THIS RFA.
PURPOSE

The objective of this Request for Applications (RFA) is to stimulate research 
on the genetic aspects of tuberculosis, exploiting advances in molecular 
biology and genomics research.  It is important to learn about the interaction 
between host and microbial genes, and to identify genes, or families of genes, 
that determine virulence, latency, reactivation of disease or resistance to 
antituberculous drugs.  Areas of particular interest are studies using novel 
biotechnologies, such as microarrays, molecular beacon technology, or 
differential signature-tagged mutagenesis (DSTM) and innovative collaborations 
with computational biologists to identify genes that mediate the pathogenesis 
of tuberculosis and elucidate the mechanisms that are responsible.   Another 
important goal of the program is to encourage junior level quantitative 
biologists to work on the genetic aspects of TB.  To facilitate their 
participation the Mentored Quantitative Research Career Development Award 
(K25) has been included as one of the mechanisms of support under this RFA.   
Among the disciplines and expertise that may be appropriate for this research 
program are genetics, molecular biology, computational biology/mathematical 
modeling, biostatistics, pathogenesis of infections, immunology, lung cell 
biology, bacteriology, pulmonology, infectious diseases, pathology, 
epidemiology, and veterinary medicine. 

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, "Genetic Aspects of 
Tuberculosis in the Lung," 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/.

ELIGIBILITY REQUIREMENTS

R01 applications may be submitted by domestic and foreign, 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 institutions only, may submit applications for K25 awards.  In 
addition, for K25 applications, former principal investigators on NIH research 
project (R01), program project (P01), center grants, FIRST Awards (R29), 
SBIR/STTR awards, sub-projects of program project (P01) or center grants, K01, 
K08 or K23 awards, or the equivalent are not eligible.  Former principal 
investigators of an NIH Small Grant (R03) or Exploratory/Developmental Grants 
(R21) remain eligible. A candidate for the Mentored Quantitative Research 
Career Development Award may not concurrently apply for any other PHS award 
that duplicates the provisions of this award nor have another application 
pending award.

Racial/ethnic minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.  All current policies and 
requirements that govern the research grant programs of the National 
Institutes of Health (NIH) will apply to grants awarded under this RFA.  
Awards under this RFA to foreign institutions will be made only for research 
of very unusual merit, need, and promise, and in accordance with PHS policy 
governing such awards.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01) and the 
Mentored Quantitative Research Career Development Award (K25) mechanisms of 
support.  A description of the K25 award is available on the web at: 
https://grants.nih.gov/grants/guide/pa-files/PA-99-087.html.  Individuals may 
apply for either an R01 grant or a K25 award under this RFA, but cannot apply 
for both grants.  Each application submitted for this RFA must be a complete, 
independent entity and not depend on any other application submitted in 
response to this RFA.

Responsibility for the planning, direction, and execution of each of the 
proposed projects will be solely that of the respective applicant.  The total 
project period for an application submitted in response to this RFA may not 
exceed 5 years.  This RFA is a one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the customary 
peer review procedures.  The anticipated award date is July 1, 2001.  

Although multidisciplinary approaches are encouraged, it is not the intent of 
this RFA to solicit applications for large studies encompassing a variety of 
individual subprojects, i.e., program projects.  If collaborative arrangements 
through subcontracts with other institutions are planned, consult the program 
staff listed under INQUIRIES.

Biomedical investigators without prior R29 or R01 support are encouraged to 
apply for R01s under this RFA and to identify their status on the front of the 
grant application.  

Specific R01 application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
https://grants.nih.gov/grants/funding/modular/modular.htm

Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research.  If so, 
a letter of agreement from either the GCRC program director or principal 
investigator should be included with the application.

FUNDS AVAILABLE


It is anticipated that for fiscal year 2001, approximately $3.5 million, total 
costs, will be committed by NHLBI and $1.0 million, total costs, will be 
committed by NIAID, for this RFA.  Award of grants pursuant to this RFA is 
contingent upon receipt of such funds for this purpose.  It is anticipated 
that up to 10-12 new R01 grants will be awarded under this program and up to 
4-6 new K25 grants will be awarded under this program.  The specific numbers 
to be funded will, however, depend on the merit and scope of the applications 
received and on the availability of funds.  

For this RFA, funds for R01s must be requested in $25,000 direct cost modules 
and a maximum of 12 modules ($300,000 direct costs) per year may be requested. 
A feature of the modular grant concept is that no escalation is provided for 
future years, and all anticipated expenses for all years of the project must 
be included within the number of modules being requested.  Only limited 
budgetary information will be required and any budget adjustments made by the 
Initial Review Group will be in modules of $25,000.  

For the K25 grants funded under this RFA, funding is determined by the 
allowable costs designated for the K25 type of award, salary of up to $75,000 
per year plus fringe benefits and research development support of up to 
$40,000 per year for the following expenses:  (a) tuition, fees, and books 
related to career development; (b) research expenses, such as supplies, 
equipment and technical personnel; c) travel to research meetings or training; 
(d) research support services including personnel and computer time.  
Ancillary Personnel Support:  Salary for mentors, secretarial, and 
administrative assistance etc., is not allowed.   Facilities and 
Administrative costs will be reimbursed at 8 percent of modified total direct 
costs.

RESEARCH OBJECTIVES

Background

Tuberculosis continues to be a worldwide health problem.  It is contagious, 
and can be difficult to diagnose and to treat.  The lung is the usual portal 
of entry for Mycobacterium tuberculosis (Mtb) and the interactions that occur 
between the microbe and the lung defense system, at all stages of the 
infection, are pivotal in determining the subsequent course of the disease.   
For decades it has been understood that inherited host resistance factors, 
genetic differences in mycobacterial virulence, and differences in 
mycobacterial sensitivity to antituberculous drugs play a large part in 
determining the way in which tuberculosis manifests itself.  Now we possess 
tools that may make it possible to elucidate the genetic control of host 
susceptibility and resistance to tuberculosis.  These new techniques may allow 
us to learn about host and microbial genes as well as the interactions between 
them and to discover which ones play a role in determining host susceptibility 
or resistance to infection and reactivation of disease as well as microbial 
virulence, latency, and resistance to antituberculous drugs.			
			
Objectives and Scope

The purpose of this RFA is to stimulate research on the genetic aspects of 
tuberculosis in the lung.  More specifically, the RFA encourages the use of 
recent technological advances in molecular biology, genomics research and 
computational biology to learn more about host and mycobacterial genes and the 
interactions between them.  The long-term goals of the RFA are to identify 
genes, or families of genes, that determine resistance and susceptibility to 
mycobacterial infection, virulence, latency, reactivation of disease and 
resistance to antituberculous drugs.  This RFA program is particularly 
relevant to African American and Hispanic minority populations who are 
disproportionately affected by tuberculosis in comparison to the total 
population, possibly because of increased genetic susceptibility.


In the last few years much progress has been made in understanding the 
genetics of the organism and the host, including: the genome of M. 
tuberculosis has been sequenced; the sequencing of the human genome is nearing 
completion; a tuberculosis resistance gene, the Bcg gene (Nramp1) has been 
identified and cloned both in mice and humans; mycobacterial genes that confer 
resistance to oxidants have been identified and cloned; and the Mtb rifampin 
resistance gene has been exploited to allow for rapid identification of drug 
resistant strains.  In addition, molecular epidemiologic methods have allowed 
a far better understanding of the spread of disease during outbreaks of 
tuberculosis.  However, much remains to be learned about the genetic factors, 
that determine interactions between the host and mycobacterium.  Genetic 
technologies now available, including genetically altered animal models and 
microarray technology, may make it possible to identify both host and 
microbial genes, or clusters of genes, that mediate the pathogenesis of 
disease and further elucidate the mechanisms that are responsible.  Skills of 
biostatisticians and other mathematicians using existing or novel mathematical 
techniques to design experimental approaches and interpret data may be 
necessary.  Understanding the molecular biology of tuberculosis should lead to 
new possibilities for controlling the disease.

In responding to this RFA expertise might be needed in the following areas: 
genetics, molecular biology, computational biology/mathematical modeling, 
biostatistics, pathogenesis of infections, immunology, lung cell biology, 
bacteriology, pulmonology, infectious diseases, pathology, epidemiology and 
veterinary medicine

This RFA is co-sponsored by NHLBI and NIAID.  NHLBI is most interested in 
encouraging research on the host lung response in M. tuberculosis infection, 
whereas NIAID is particularly interested in using this RFA to encourage 
research on the microbial genome and post genomic functional analysis to 
better understand TB pathogenesis.  Of great interest to both NIAID and NHLBI 
are genes associated with latency and reactivation of disease, and with host-
microbe interaction.

Some examples of areas of research that might be included under this RFA are 
as follows:

o   Studies of gene expression in M. tuberculosis in animal (e.g. mouse, non-
human primate, etc.) or human macrophages and other host cells during 
infection, using novel technologies such as molecular beacon RT-PCR, DNA 
microarrays, non-invasive imaging techniques (biophotonics) or any combination 
of these or other approaches.  Such studies might address issues relating to 
metabolic state/stage of infection and therapeutic interventions.

o   Study genetic variations in M. tuberculosis and BCG and their relevance to 
patterns of disease and efficacy of vaccination.

o   Population based studies to analyze novel biologic characteristics of 
clinical strains of  M. tuberculosis, as well as to study the human immune 
response to infection in a situation where a group of people are all infected 
with a single strain of M. tuberculosis.  Can microbial and host genetic 
factors be identified that help to explain why some people develop 
tuberculosis, some convert their PPD skin reaction, some revert to PPD 
negativity?  Investigators are encouraged to use already identified cohorts.

o   Studies in mice or other animal models to determine the differences of 
host cell gene expression in response to mycobacterial infection, in lung as 
compared to other organs (e.g., lung, liver, spleen, kidney) or in upper as 
compared to lower lung zones.

o   Studies in structural genomics, such as studies to determine protein 
structure and function of the entire set of gene products from the 
tuberculosis genome or identification of protein families involved in the 
pathogenesis of tuberculosis.


o   Use of genetically manipulated (e.g., transgenic, knock out) animals and 
novel biotechnologies to study the pathogenesis of pulmonary tuberculosis, and 
the factors that contribute to innate resistance to M. tuberculosis, to 
latency and to reactivation.

o   Studies involving collaboration with mathematicians (e.g., computational 
biologists) to develop new paradigms for examining interactions between the 
mycobacterial and host genomes.

These are examples only.  Investigators should not feel limited to the 
subjects mentioned above and are encouraged to submit other topics pertinent 
to the objectives of the RFA. 

Two additional goals of the RFA specific to the Mentored Quantitative Research 
Career Development Award, K25 awards, are as follows:

o   Encourage research-oriented quantitative scientists and engineers with 
little or no experience in biology or biomedicine to develop independent 
research skills and gain experience in advanced methods and experimental 
approaches that will allow them to conduct basic or clinical biomedical 
research related to the genetic aspects of tuberculosis or to play leading 
roles in multi-disciplinary research teams. 

o   Increase the pool of quantitative researchers who can conduct biomedical 
research related to the genetic aspects of tuberculosis in the lung, 
capitalizing on the quantitative backgrounds of the investigators to inform 
new directions in this area of research. 

SPECIAL REQUIREMENTS

K25 applicants must fulfill the eligibility requirements for the K25 award 
described at https://grants.nih.gov/grants/guide/pa-files/PA-99-087.html    
Special requirements for the K25 award pertain to the candidate, the 
mentor(s), the program, the environment and possible future evaluations.

Upon initiation of the program, the NHLBI and NIAID will sponsor periodic 
meetings to encourage exchange of information among all funded investigators 
who participate in this program.  A major goal of these meetings is to 
facilitate progress by providing a forum that will lead to sharing ideas, 
technology, data, skills, and biological materials.  Applicants for both K25 
and R01 awards must budget for travel funds that will allow principal 
investigators and other key research scientists to participate in these 
meetings.  The meetings are usually one day meetings, held each year, in 
Bethesda, Maryland. Applicants must include a statement in their applications 
indicating their willingness to participate in these meetings.

Animal models based on genetic manipulations (e.g., transgenic and knock out 
animals) are encouraged.  Multidisciplinary approaches that include 
mathematical modeling are of particular interest.  Research on human tissue is 
encouraged, however, large clinical or population based studies are not within 
the scope of this RFA. 

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 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
https://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: https://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 November 1, 2000, a letter of 
intent that includes a descriptive title of the proposed research, the type of 
application proposed (R01 or K25), 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 subsequent applications, the information that it 
contains allows NHLBI staff to begin to identify appropriate reviewers, to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Deborah P. Beebe listed under 
INQUIRIES by November 1, 2000.

APPLICATION PROCEDURES


The research grant application form PHS 398 (rev.4/98) is to be used in 
applying for these grants.  These forms 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 301/710-0267, 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 (GENETIC ASPECTS OF TUBERCULOSIS IN THE LUNG) and number (HL-00-014) 
must be typed on line 2 of the face page of the application form and the YES 
box must be marked. 

The sample RFA label available at: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has 
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 be 
sent to Dr. Deborah P. Beebe, at the address listed under INQUIRIES.

Applications must be received by the application receipt date listed in the 
heading of this RFA, January 17, 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 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.

SPECIFIC INSTRUCTIONS FOR R01 APPLICANTS

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.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below. 

BUDGET INSTRUCTIONS FOR R01 APPLICATIONS


Modular grant applications will request direct costs in $25,000 modules, up to 
a total direct cost of $300,000 per year for all R01s.  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 $300,000) 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 - Prepare a Modular Grant Budget Narrative 
page. (See https://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.  This is not a Form page.

o Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

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.  Include the Letter of 
Intent to establish a consortium.

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:  
https://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;


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. All appropriate exclusions must be applied  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. 

o  OTHER SUPPORT - Do not complete the "Other Support" pages.  Selected other 
support information relevant to the proposed research may be included in the 
Biographical Sketch as indicated above. Complete Other Support information 
will be requested by NHLBI staff if there is a possibility for an award.

SPECIFIC INSTRUCTIONS FOR K25 APPLICATIONS

An important goal of this RFA is to stimulate collaborations between 
quantitative scientists and biological scientists to investigate the genetics 
of tuberculosis.  We want to encourage junior level quantitative biologists to 
do research on the genetics of TB.  For this reason the K25 program, which 
fosters career development of mathematicians and engineers interested in 
biomedical research, has been included as a funding mechanism under this RFA. 
Some information on eligibility criteria for the K25 is summarized below.  
However, THOSE INTERESTED IN APPLYING FOR K25 AWARDS WILL NEED TO OBTAIN 
ADDITIONAL INFORMATION ON THE K25 GOALS, ELIGIBILITY, RESTRICTIONS AND SPECIAL 
REQUIREMENTS FROM THE K25 PROGRAM ANNOUNCEMENT, WHICH CAN BE FOUND AT: 
https://grants.nih.gov/grants/guide/pa-files/PA-99-087.html. 

The K25 awards are NOT modular.  Applications for K25 awards under this RFA 
must use the RFA receipt date of January 17, 2001, NOT the application receipt 
dates stated in the PA-99-087.  The K25 application budgets should be prepared 
in accordance with the allowable costs and instructions provided in PA-99-087. 
The K25 applications must follow the K25 guidelines and comply with the 
requirements for the K25.  Just-in-time instructions apply to both the R01 and 
K25 mechanisms.

o Special eligibility requirements apply to K25 Candidates applying for this 
RFA: They must have demonstrated research interests with an advanced degree in 
a quantitative area of science or engineering: M.S.E.E., Ph.D., D.Sc., etc. 
They must identify a mentor with extensive biomedical and/or computational 
biology research experience.  The K25 candidates must be willing to spend at 
least 75 percent of full-time professional effort conducting research career 
development and basic or clinical research.  K25 applicants experience in 
biomedical research may vary.  Some may have very limited experience in 
biomedical research and require didactic training and a very closely 
supervised research experience.  Other K25 applicants, with more experience, 
may require less class work and less supervision.  Applications may be 
submitted on behalf of candidates, by DOMESTIC organizations, public or 
private, such as research foundations, research institutions, commercial 
entities, medical, dental, or nursing schools, Federal National Laboratories 
(except for laboratories of the National Institutes of Health), or other 
institutions of higher education.  At time of the K25 AWARD, CANDIDATES MUST 
BE CITIZENS OR NONCITIZEN NATIONALS OF THE UNITED STATES, OR HAVE BEEN 
LAWFULLY ADMITTED TO THE UNITED STATES FOR PERMANENT RESIDENCE (I.E., IN 
POSSESSION OF A CURRENTLY VALID ALIEN REGISTRATION RECEIPT CARD I-551, OR 
OTHER LEGAL VERIFICATION OF SUCH STATUS).   Noncitizen nationals are generally 
persons born in outlying possessions of the United States (i.e., American 
Samoa and Swains Island).  Individuals on temporary or student visas are not 
eligible.


o FORMER PRINCIPAL INVESTIGATORS on NIH research project (R01), program 
project (P01), center grants, FIRST Awards (R29), SBIR/STTR awards, 
sub-projects of program project (P01) or center grants, K01, K08 or K23 
awards, or the equivalent are NOT ELIGIBLE FOR THE K25 AWARD. FORMER PRINCIPAL 
INVESTIGATORS of an NIH Small Grant (R03) or Exploratory/Developmental Grants 
(R21) REMAIN ELIGIBLE. A candidate for the Mentored Quantitative Research 
Career Development Award may not concurrently apply for any other PHS award 
that duplicates the provisions of this award nor have another application 
pending award. Mentored Quantitative Research Career Development Award 
recipients are strongly encouraged to apply for independent research grant 
support, either Federal or private, during the latter period of this K25 
award.  However, since the K25 is a full professional effort award, time 
conducting additional research directly related to this award is subsumed 
under the salary support already provided by this award.

THE K25 APPLICATION MUST CONTAIN THE FOLLOWING:

Candidate (K25)

o  A description of the candidate's commitment to a career in quantitative 
biomedical, behavioral, or bioengineering research

o  Evidence of the candidate's interest in conducting research

o  Evidence of the candidate's potential to develop into an independent 
investigator

o  A description of immediate and long-term career objectives, explaining how 
the award will contribute to their attainment

o  A commitment of at least 75 percent effort to this research program

o  Three sealed letters of recommendation addressing the candidate's potential 
for a research career in quantitative biomedicine or bioengineering. The 
mentor's statement (see below) should not be included as one of the letters of 
recommendation, although the mentor(s) may submit a separate letter(s) of 
recommendation.

Career Development Plan (K25)

o  A description of the career development plan, incorporating consideration 
of the candidate's goals and prior experience.  It must describe a systematic 
plan to obtain the necessary theoretical and conceptual background, in 
addition to the research experience, necessary to launch an independent 
research career in quantitative biomedicine or bioengineering.

o  Candidates must describe the availability of courses important to their 
career development plan at their institution and the manner of integration of 
these studies into their career development plan.

o  The career development plan must be tailored to the needs of the individual 
candidate and the ultimate goal of achieving independence as a researcher in 
quantitative biomedicine or bioengineering.  Less experienced candidates may 
require a phased developmental period in which the first one to two year(s) of 
the award are largely of a didactic nature followed by a period of intense, 
supervised research. Candidates with more experience at the time of 
application may need a shorter developmental period and may already have an 
adequate theoretical background. 


o  Candidates must describe plans to receive instruction in the responsible 
conduct of research. These plans must detail the proposed subject matter, 
format, frequency, and duration of instruction.  No award will be made if an 
application lacks this component.

Research Plan (K25)

o  A description of the quantitative biomedical, behavioral, or bioengineering 
research plan. The research plan must be described as outlined in form PHS 
398, including sections on the Specific Aims, Background and Significance, 
Progress Report/Preliminary Studies, Research Design and Methods.  The 
candidate should consult with the mentor regarding the development of this 
section.

Mentor's Statement (K25)

o  The application must include information on the mentor(s), including 
information on basic or clinical biomedical research qualifications in the 
research area proposed by the candidate and previous experience as a research 
supervisor.  The application must also include information to describe the 
nature and extent of supervision that will occur during the proposed award 
period.  Mentors may be employed in any sector of the biomedical research 
community (e.g., academia, industry, non-profit research institutions). 

Environment and Institutional Commitment (K25)

o  The sponsoring institution must document a strong, well-established 
research and training program related to the candidate's area of interest, 
including a high-quality research environment with staff capable of productive 
collaboration with the candidate. The sponsoring institution also must provide 
a statement of commitment to the candidate's development into a productive, 
independent investigator. 

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by the NHLBI and NIAID.  Incomplete and/or non-responsive 
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 NHLBI in accordance with the review criteria stated below.  The roster of 
reviewers for the RFA will be available on the NHLBI home page approximately 
four weeks prior to the scheduled review date.  As part of the initial merit 
review, a process will be used by the initial review group in which all 
applications 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 Heart, Lung, 
and Blood Advisory Council or the National Institute of Allergy and Infectious 
Diseases Advisory Council.

REVIEW CRITERIA FOR R01 APPLICATIONS

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 review, comments on the following aspects of the application will 
be made 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.

(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 personnel category will be reviewed for appropriate staffing based on the 
requested percent effort and justification provided.  For R01 applications, 
the direct costs budget request will be reviewed for consistency with the 
proposed methods and specific aims.  Any budgetary adjustments recommended by 
the reviewers will be in $25,000 modules.  The duration of support will be 
reviewed to determine if it is appropriate to ensure successful completion of 
the requested scope of the project.


REVIEW CRITERIA FOR K25 APPLICATIONS:

The following review criteria will be applied:

Candidate

o  Quality of the candidate's academic and research record; 

o  Potential to develop as an independent quantitative biomedical or 
bioengineering researcher or to play significant role in multi-disciplinary 
research teams; and 

o  Commitment to a career in quantitative biomedical or bioengineering 
research.
Career Development Plan

o  Likelihood that the career development plan will contribute substantially 
to the scientific development of the candidate;


o  Appropriateness of the content and duration of the proposed didactic and 
research phases of the award;

o  Consistency of the career development plan with the candidate's career 
goals and prior research experience; and

o  Quality of the proposed training in responsible conduct of research.

Research Plan

Reviewers recognize that an individual with limited research experience is 
less likely to be able to prepare a research plan with the breadth and depth 
of that submitted by a more experienced investigator.  Although it is 
understood that K25 applications do not require the level of detail necessary 
in regular research grant applications, a fundamentally sound research plan 
must be provided. In general, less detail is expected with regard to research 
planned for the later years of the award, but the application should outline 
the general goals for these years.

o  Appropriateness of the research plan to the stage of research development 
and as a vehicle for developing the research skills as described in the career 
development plan;

o  Scientific and technical merit of the research question, design and 
methodology;

o  Relevance of the proposed research to the candidate's career objectives;

o  Adequacy of the plan's attention to gender and minority issues associated 
with projects involving human subjects; and

o  Adequacy of plans for including children as appropriate for the scientific 
goals of the research, or justification for exclusion.

Mentor

o  History of research productivity and support in the area of basic or 
clinical biomedical research; 

o  Appropriateness of mentor's research qualifications in the area of this 
application;

o  Quality and extent of mentor's proposed role in providing guidance and 
advice to the candidate; and

o  Previous experience in fostering the development of researchers.

Environment and Institutional Commitment

o  Applicant institution's commitment to the scientific development of the 
candidate and assurances that the institution intends the candidate to be an 
integral part of its research program; 

o  Adequacy of research facilities and the availability of appropriate 
educational opportunities (including access to such facilities or 
opportunities in other institutions);


o  Quality and relevance of the environment for scientific and professional 
development of the candidate; and 

o  Applicant institution's commitment to an appropriate balance of research 
and other responsibilities.

Budget

o  Justification of the requested budget in relation to career development 
goals and research aims.

In addition to the above criteria, in accordance with NIH policy, all R01 and 
K25 applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders and minorities and their 
subgroups as appropriate for the scientific goals of the research will be 
reviewed.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  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.

SCHEDULE

Letter of Intent Receipt Date:  November 1, 2000
Application Receipt Date:       January 17, 2001
Council Review:                 June 14-15, 2001	
Anticipated Start Date:         July 1, 2001

AWARD CRITERIA

Award criteria that will be used to make award decisions include:
o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

Applicants should be aware that, in addition to scientific merit, program 
priorities and program balance, the total costs of the proposed project and 
the availability of funds will be considered by the awarding Institutes in 
making funding recommendations.  The Institutes may fund individual 
applications based on a number of considerations, the most important of which 
are based on their scientific merit and their importance in meeting the 
objectives of the RFA.  Applications from new investigators will be strongly 
considered.

INQUIRIES

Inquiries concerning this RFA are strongly encouraged.  Potential applicants 
should request a copy of the sample budget pages. The opportunity to clarify 
any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail:  peavyh@nih.gov

Or

Susan Garfinkel, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail: garfinks@nih.gov

Or

Ann M. Ginsberg, M.D., Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, room 3131, MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
Email: ag73i@nih.gov 

Direct inquiries regarding fiscal matters (e.g., sample budget pages) to:

Ms. Tara Mowery
Division Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7163, MSC 7926
Bethesda, MD  20892-7926
Telephone: (301) 435-5081
FAX: (301) 480-3310
Email: moweryt@nhlbi.nih.gov

Inquires regarding review, letters of intent and two copies of the grant 
application should be directed to:

Deborah P. Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0270
FAX:  (301) 480-3541
E-mail: beebed@nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance, Nos. 
93.838 and 93.361.  Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 UC241 and 284) and 
administered under PHS grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 72 and CFR 52 and 45 CFR Part 74 for NIAID. This program 
is not subject to the intergovernmental review requirements of Executive Order 
12372 or a 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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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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