SUSCEPTIBILITY TO TARGET ORGAN DAMAGE IN HIGH BLOOD PRESSURE

Release Date:  January 16, 2001

RFA:  RFA-HL-01-002

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov)

Letter of Intent Receipt Date:  February 13, 2001
Application Receipt Date:       March 13, 2001

PURPOSE

The purpose of this solicitation is to encourage basic research to identify 
genetic and other biological factors that increase the susceptibility to 
hypertension-related injury and damage to target organs.  Two broad scientific 
areas will be considered responsive to this Request For Applications (RFA): 
(1) mapping and identification of genes responsible for the susceptibility to 
target organ damage associated with high blood pressure in humans or animal 
models, and (2) mechanistic studies on the biological consequences of 
variations of these genes and on the interaction of genetic and non-genetic 
factors that modulate the susceptibility to target organ damage.  Innovative, 
multidisciplinary approaches are encouraged, especially integrative molecular, 
cellular, and whole animal studies which can be applied to the human 
condition.

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, Susceptibility to Target Organ 
Damage in High Blood Pressure, 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

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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This Request for Applications (RFA) will use the National Institutes of Health 
(NIH) individual research project grant (R01) award mechanism.  Responsibility 
for the planning, direction, and execution of the proposed project will be 
solely that of the applicant.  In accordance with the policy of the National 
Heart, Lung, and Blood Institute, the total project period for an application 
submitted in response to this RFA may not exceed four years.  However, a fifth 
year may be considered in exceptional circumstances, but solely for studies on 
human subjects, if the request is strongly justified in the grant application 
and viewed enthusiastically by peer review.  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 
September 30, 2001.

FUNDS AVAILABLE

The NHLBI intends to commit $2.625 million in FY 2001 to fund four to six new 
grants in response to this RFA.  An applicant may request a project period of 
up to four years and a budget for direct costs of up to $500,000 per year.  A 
fifth year may be requested only for studies on human subjects if strongly 
justified, and then may be considered for funding if the peer review level of 
enthusiasm is very high.  Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will also 
vary.  Although the financial plans of the Institute provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications. 

RESEARCH OBJECTIVES

Background

Damage to target organs is the principal source of morbidity and mortality 
associated with high blood pressure.  Untreated and inadequately controlled 
hypertension leads to a reduction in organ function and is a major risk factor 
for a variety of end organ diseases such as left ventricular hypertrophy 
(LVH), myocardial ischemia, intraparenchymal cerebral ischemia, and end-stage 
renal disease (ESRD).   

The public health aspects of hypertensive target organ damage are staggering. 
  For example, there are 300,000 ESRD patients in the United States, at a 
total cost for care of $16 billion.  The incidence of new cases has been 
increasing at six percent per year, and a quarter of ESRD patients also are 
diagnosed with hypertension.  200,000 people die of myocardial infarction in 
the US per year.  Hypertensive patients not only have an increased incidence 
of myocardial infarction, but also have an increased likelihood of 
complications and a reduced survival rate after myocardial infarction.  The 
prevalence of hypertension is approximately 60 percent of patients with 
chronic angina pectoris, which is the classic manifestation of myocardial 
ischemia.  There are 600,000 new and recurrent cases of stroke and 160,000 
deaths due to stroke in the US per year.  Ten to twenty percent of these 
deaths are due to intraparenchymal hemorrhage in the brain that is directly 
related to high blood pressure.  In addition, other types of stroke are 
indirectly caused by hypertension. 

Traditional pathophysiologic studies have made some inroads into the 
mechanisms underlying organ injury associated with hypertension.  However, 
these studies do not explain the differences in prevalence and disease 
intensity among different ethnic groups, such as the disproportionately large 
representation of African Americans with ESRD and stroke.  Moreover, it is not 
understood why individuals with comparable levels and duration of high blood 
pressure manifest damage to different organs and vary greatly in their 
vulnerability to, and intensity of, organ injury.  

The factors responsible for varying susceptibility to organ injury are not 
understood, although animal studies suggest a strong genetic contribution.  
Modern molecular technologies and new animal models have made the genetic 
identification of susceptible individuals a feasible goal.  To date, at least 
five separate chromosomal quantitative trait loci (QTLs) have been linked to 
chronic renal failure in the rat, and one of these loci has been mapped to 
homologous regions in the human genome.  A recent human study found a 
significant association of hypertensive-ESRD with one of the sodium-hydrogen 
exchanger (NHE) genes.  Another human study revealed QTLs on three chromosomes 
that are linked to hypertension-induced LVH.  A few small studies have 
discovered genetic abnormalities in specific clinical populations, such as an 
angiotensinogen polymorphism found for LVH in endurance athletes.  Innovative 
genetic, genomic, and pathophysiologic studies are needed to discover new 
pathways that lead to organ injury and damage.

Clearly, there is a need to determine which forms of organ damage are 
independent of the severity of high blood pressure and which forms have an 
absolute requirement for hypertension.  There are forms of organ injury that 
do not recede in severity when blood pressure is decreased with medication.  
Careful studies should also be conducted on the extent to which organ damage 
and hypertension exacerbate each other in a vicious cycle.  The elucidation of 
these factors will help determine preventive and therapeutic strategies to 
reduce clinical morbidity and mortality.

Objectives and Scope

The objectives of this program are to identify and analyze genetic and other 
biological factors and their interactions that increase susceptibility to 
hypertension-related injury and damage to target organs such as the kidney, 
heart, and brain.  Two broad scientific areas will be considered responsive to 
this RFA: (1) mapping and identification of genes responsible for the 
susceptibility to target organ damage associated with high blood pressure in 
humans or animal models, and (2) mechanistic studies on the biological 
consequences of variations of these genes and on the interaction of genetic 
and non-genetic factors that modulate the susceptibility to target organ 
damage. 

Emerging evidence of gene-gene interactions suggest that >modifier= genes that 
are not pathogenic by themselves appear to intensify or reduce the pathogenic 
expression of other genes.  Moreover, abnormalities in gene regulation play an 
important role in organ injury and damage.  In addition, heritable factors are 
often modified by environmental factors, such as diet, exercise, toxins, and 
physical and mental stress.  The challenge to researchers has been the 
quantitation of these factors in individuals.  Dietary salt is relatively 
amenable to quantitation, and animal studies provide convincing evidence that 
a high salt intake contributes to increased arterial pressure and target organ 
injury.  Furthermore, in salt-sensitive rats, after renal damage has already 
occurred as a result of hypertension, a reduction of salt intake does not 
necessarily lower blood pressure.  Thus, it is important to identify markers 
or predictors of early organ injury in order to arrest its development into 
irreversible damage.  

New molecular genetic technologies such as cDNA microarrays that detect 
multiple differential gene expressions at one time provide new opportunities 
for this complex field of research.  Additional animal models using state-of-
the-art methods such as congenics, consomics, and targeted gene expression 
should also be helpful.

Since hypertension is a complex, multifactorial disorder, its associated 
target organ damage is expected to be complex as well.  A new challenge to 
researchers is to address the interrelationships of concomittant genetic, 
biologic, and environmental factors.  Therefore, the search for susceptibility 
factors calls for innovative multidisciplinary approaches, including 
physiology, molecular and cell biology, and genetics, that can be effectively 
translated to the human condition.

SPECIAL REQUIREMENTS

Although small, basic studies using human subjects are suitable for this RFA, 
large scale clinical trials and epidemiological studies will not be considered 
responsive.

Upon initiation of the program, the NHLBI will sponsor annual meetings to 
encourage exchange of information among investigators who participate in this 
program.  In the budget development, applicants should include funds for 
annual one-day grantees= meetings, most likely in Bethesda, Maryland.  
Applicants should also include a statement in their applications indicating 
their willingness to participate in these meetings.

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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a 
complete copy of the updated Guidelines are available at  
http://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: http://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 a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  Although a letter of 
intent is not required, is not binding, and does not enter into the review of 
a subsequent application, the information that it contains allows the 
Institute or Center staff to estimate the potential review workload and plan 
the review.

The letter of intent is to be delivered by mail or fax by February 13, 2001, 
to Deborah Beebe, Ph.D., at the address listed under INQUIRIES.

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.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf  has been modified to 
allow for this change.  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 Deborah Beebe, Ph.D., at the address listed under INQUIRIES.

Applications must be received by March 13, 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.  All 
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.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Heart, Lung, and Blood Advisory Council.

Review Criteria

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

(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 
methods? 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?

(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?

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

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  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.  Specifically, if a fifth year is requested for human 
studies, the appropriateness and adequacy of the justification will be 
evaluated.

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:    February 13, 2001
Application Receipt Date:         March 13, 2001
Peer Review Date:                 June/July, 2001
Council Review:                   September 6-7, 2001
Earliest Anticipated Start Date:  September 30, 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.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.  Applicants 
with projects involving human subjects are strongly encouraged to contact the 
program administrator listed below.

Direct inquiries regarding programmatic issues to:

Winnie Barouch, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10193, MSC 7956
Bethesda, MD  20892-7956
Telephone: (301)435-0560
FAX: (301)480-2849
Email: BarouchW@nhlbi.nih.gov

Direct inquiries regarding review issues, send letter of intent and two copies 
of the application to:

Deborah Beebe, Ph.D.
Chief, Review Branch
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
Email: BeebeD@nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Beckie Chamberlin
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7166, MSC 7926
Bethesda, MD  20892-7926
Telephone: (301)435-0155
FAX: (301)480-3310
Email: ChamberR@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.837.  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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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.  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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