GENETIC MODIFIERS OF MENDELIAN DISEASES OF INTEREST TO NIDDK
 
RELEASE DATE:  November 19, 2002
 
RFA: DK-03-008
 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (www.niddk.nih.gov)
 
LETTER OF INTENT RECEIPT DATE:  February 11, 2003

APPLICATION RECEIPT DATE:  March 11, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA

The National Institute of Diabetes and Digestive and Kidney Diseases invites 
research applications to identify and characterize genetic modifiers for 
Mendelian diseases affecting organs and tissues within the mission of NIDDK.  
Striking variations are seen in clinical expression of genetic diseases, 
presumably due to differences in the genetic makeup and environmental 
exposure of the individual.  Even though a mutation in a single gene may play 
a predominant role in the development of a Mendelian disorder, individuals 
with identical genotypes at that locus may display considerable variation in 
the prevalence, severity, and clinical symptoms of the disorder.  To 
understand this variation and to exploit it as a target for therapy, it is 
important to identify genes or other factors that contribute to this 
variation.
 
RESEARCH OBJECTIVES
 
Background

On September 9 and 10, 2002, NIDDK sponsored a meeting entitled, "Genetic 
Modifiers of Mendelian Diseases" highlighting progress toward the 
identification of modifier genes in diseases of interest to NIDDK.  
Investigators described approaches to identifying genetic modifiers and 
presented the clinical evidence for the presence of significant modifiers for 
several genetic diseases.  Additional information on the presentations can be 
found in the abstracts at 
http://www.niddk.nih.gov/fund/other/genetic/gmmt/abstract-book.pdf 

Many genetic diseases within the mission of NIDDK have evidence for 
clinically significant genetic modifiers.  Some examples of these diseases 
are genetic metabolic diseases such as Gaucher disease, adrenoleukodystrophy 
and cystic fibrosis; genetic hematologic diseases such as thalassemia, sickle 
cell disease and hemochromatosis; genetic liver diseases such as alpha-1-
antitrypsin deficiency and Wilson disease; genetic pancreatic diseases such 
as hereditary pancreatitis; and genetic kidney diseases such as polycystic 
kidney disease. A complete description of the diseases of interest to NIDDK 
can be found on the NIDDK Website (http://www.niddk.nih.gov/fund/fund.htm#1)and 
several illustrative examples are included below.

Hemochromatosis is a common, recessively inherited disease of iron overload.  
Increased iron storage, particularly in the liver, leads to the clinical 
sequelae of cirrhosis, diabetes and cardiomyopathy, but the iron accumulation 
and the associated clinical presentation can be highly variable, even within 
one family.  Most patients with the disease have been shown to have mutations 
in the HFE gene with the predominant mutation being a missense mutation, 
C282Y.  However, population studies have found that only a small percentage 
of those who are homozygous for this HFE mutation have clinical features of 
hemochromatosis. It appears most likely that other genetic factors are 
involved in modifying the expression of the gene, although some environmental 
factors may play a role.  The obvious candidate genes are those encoding 
proteins known to be important in iron transport, but it is not known to what 
degree variations in the iron transport genes contribute to the clinical 
presentation of hemochromatosis and other iron disorders. Although several 
important genes of iron transport have been identified in recent years, there 
may be others not yet discovered that impact on the expression of 
hemochromatosis. 

Another explanation for diseases that appear to show reduced penetrance such 
as hemochromatosis and Gaucher disease, may be the presence of a genetic 
suppressor of the disease phenotype.  This is an intriguing possibility since 
identification of a suppressor gene could lead to new targets for therapy.

Cystic Fibrosis is one of the most common, life-limiting genetic diseases in 
children.  The predominant mutation, deltaF508, results in the deletion of a 
single amino acid in the CFTR protein.  Approximately 90% of CF patients 
carry at least one deltaF508 mutation.  Despite the presence of a predominant 
mutation, there is a large variation in the clinical severity of this 
disease.  Meconium ileus is a severe intestinal obstruction that occurs at 
birth in 15-20% of CF patients.  In a CF mouse model, a modifier gene was 
detected on mouse chromosome 7 that contributed to fatal intestinal disease.  
In humans, there is strong evidence for a modifying locus linked to 19q13, 
syntenic to a region of mouse chromosome 7 which contains a modifier 
contributing to fatal intestinal disease.  Candidate genes in this region are 
being studied to identify the gene or genes responsible for this phenotype.  
The identification of this modifier gene could lead to better understanding 
of the factors underlying the clinical heterogeneity in CF.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most 
common Mendelian diseases in humans and a major cause of renal failure.  
ADPKD patients present with progressive, bilateral cysts in the kidney.  
Other common symptoms include hypertension, liver cysts and intracranial 
aneurysms.  Symptoms commonly appear in midlife but have been known to occur 
in childhood.  Modifier genes may contribute to the variable age of onset 
seen in this disease.  Genetic modifiers for severity of the renal disease 
have been mapped in two animal models of PKD but have not been yet been 
studied in humans.  Modifier genes have also been implicated in the 
occurrence of intracranial aneurysms, which are found in approximately 10% of 
patients with ADPKD.  This complication has been shown to cluster in some PKD 
families.

Alpha-1-antitrypsin (AAT) deficiency is a recessive genetic disease affecting 
both the lung and the liver.  Alpha-1-antitrypsin is a protease inhibitor 
made by the liver and by alveolar macrophages.  Deficiency of this enzyme 
produces obstructive lung disease and liver fibrosis.  The lung disease is 
caused by destruction of lung tissue by proteases such as elastase that are 
released by macrophages but not properly inactivated when AAT is absent. The 
liver disease, in contrast, seems to be caused by aggregation of the 
defective alpha-1-antitrypsin protein in the endoplasmic reticulum of the 
hepatocytes.  Since the pathophysiology is different for the lung disease and 
the liver disease, not all mutations of AAT lead to both problems.  
Approximately 17% of patients homozygous for the common Pi*Z mutation have 
liver disease.  This observation suggests that a genetic modifier may 
contribute to the liver disease phenotype.  

Many of the examples cited above have organ-specific phenotypes such as 
meconium ileus in CF, aneurysm in ADPKD and liver disease in AAT that seem to 
be influenced by genetic modifiers.  Since the organ-specific phenotypes 
occur in a significant proportion of the patient population, the genetic 
modifiers for these phenotypes must be fairly common in the general 
population.  These modifiers may also contribute to other genetic diseases or 
complex disease conditions affecting the same organ.  Identification of 
organ-specific modifier genes may lead to an understanding of genetic risks 
for other more common conditions and provide new targets for the development 
of diagnostic tests and therapeutics. 

Scope

This initiative is soliciting research grant applications to identify 
modifier genes responsible for variation in the clinical presentation of 
genetic Mendelian diseases affecting organs and tissues of interest to NIDDK.  
Approaches to characterize putative modifier genes could include studying 
either physiological or positional candidate genes as well as the development 
of analytical and computational tools to systematically investigate the 
genetic and physiologic control of relevant traits and diseases.  Following 
the identification of the modifier gene, these studies should characterize 
the allelic variants of these gene(s), and determine which variants are 
responsible for the phenotypic variation.  

Mouse models of genetic diseases provide a powerful tool to demonstrate the 
effect of modifier genes.  By breeding the main genetic defect onto different 
background strains of mice, the severity of the phenotype of the genetic 
disease can be altered.  This approach has been used to identify regions that 
may contain genetic modifiers.  This approach will become more powerful as 
the DNA sequences of different inbred mouse strains become available for 
analysis.  In addition, random mutagenesis could be used to screen for 
genetic modifiers in mouse strains bearing a disease-predisposing mutation.

Other model systems such as Drosophila and zebrafish have been used to screen 
for modifier genes for particular phenotypes.  These models could be 
developed to screen for modifier genes that contribute to human genetic 
diseases.  These models are ideal for identifying pathways that influence a 
phenotype generating candidates for modifier genes.

Careful phenotyping of patient populations can also lead to the 
identification of genetic modifiers.  For these studies, the applicants must 
be able to demonstrate the availability of well-characterized patient 
populations in which the variation can be evaluated.  In order to be able to 
accurately phenotype individuals as well as carry out the genetic analysis 
each project should include effort for individuals who have clinical 
experience in the disease as well as individuals with experience in 
genotyping and statistical genetics.  Genotype/phenotype studies may be 
performed to reveal the degree to which disease severity can be attributed to 
allelic differences or gene environment interactions.  

The following examples, while not an exhaustive list, are relevant to the 
goals of this initiative:

o Studies in animal models of Mendelian diseases to identify genetic 
modifiers of disease loci

o Developing sensitized mutagenesis screens to search for mutations that 
modify the disease phenotype

o Using model systems to identify interacting pathways or networks to use as 
candidate genes for the identification of modifier genes

o Studies in human populations, including twin or family studies, to identify 
aspects of a disease phenotype that are inherited independently of the 
disease gene mutation 

o Studies in human population that use genome-wide screening techniques, such 
as SNP typing and microarray technology, to identify regions, genes or 
pathways involved in development of the clinical variation

o Studies in humans and animals demonstrating the presence of an 
independently inherited suppressor of the disease phenotype 

o Studies of genes involved in regulating cellular processes such as DNA 
transcription, RNA processing, protein modification, protein folding, 
trafficking to the membrane, and RNA and protein degradation as likely 
candidates for genetic modifiers of diseases

o The development of analytical and computational tools as well as public 
databases to integrate information on genetic variability and to 
systematically investigate the genetic and physiologic control of relevant 
traits and diseases on genetically defined populations.

MECHANISM OF SUPPORT
 
This RFA will use NIH regular research grant (R01) award mechanism.  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project will 
compete with all investigator-initiated applications and will be reviewed 
according to the customary peer review procedures. The anticipated award date 
is September 30, 2003.

This RFA 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.

FUNDS AVAILABLE 
 
The NIDDK intends to commit approximately $3,000,000 in FY 2003 to fund 6 to 
8 grant applications in response to this RFA. An applicant may request a 
project period of up to 5 years and a budget for direct costs of up to 
$500,000 per year. Because the nature and scope of the proposed research will 
vary from application to application, it is anticipated that the size and 
duration of each award will also vary. Although the financial plans of the 
IC(s) 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. At this time, it is not known if this RFA 
will be reissued. 
 
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 inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research, and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Catherine McKeon. Ph.D.
Senior Advisor for Genetic Research
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm.6103 
Bethesda, MD  20892-5460
Telephone:  (301) 594-8810
FAX:  (301) 480-3503
Email: cm67w@nih.gov 

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

Kathleen Shino
Supervisory Grants Management Specialist
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm.708
Bethesda, MD 20892-5452
Telephone:  (301) 594-8869
FAX: (301) 480-3504
Email: ks48e@nih.gov 
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 IC staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Catherine McKeon. Ph.D.
Senior Advisor for Genetic Research
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm.6103 
Bethesda, MD  20892-5460
Telephone:  (301) 594-8810
FAX:  (301) 480-3503
Email: cm67w@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.
 
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.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
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 RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
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 the application 
receipt date listed in the heading of this RFA.  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.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK Staff.  Incomplete applications will be returned 
to the applicant without further consideration.  And, if the application is 
not responsive to the RFA, CSR staff may contact the applicant to determine 
whether to return the application to the applicant or submit it for review in 
competition with unsolicited applications at the next appropriate NIH review 
cycle.

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 NIH in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will:

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the National Diabetes, Digestive and 
Kidney Diseases 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 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:

o 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.

o 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)

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  February 11, 2003
Application Receipt Date:  March 11, 2003
Peer Review Date:  July 2003
Council Review:  September 24-25,2003
Earliest Anticipated Start Date:  September 30, 2003

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.
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research projects unless a 
clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with 
the new OMB standards; clarification of language governing NIH-defined Phase 
III clinical trials consistent with the new PHS Form 398; and updated roles 
and responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 RFA 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.

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 
RFA 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. 93.847 and 93.849, 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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