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Release Date:  June 14, 1999

PA NUMBER:  PA-99-110

National Institute on Alcohol Abuse and Alcoholism



The Division of Basic Research of the National Institute on Alcohol Abuse and
Alcoholism (NIAAA) invites grant applications that focus on the developmental
mechanisms of hepatic fibrosis that occur in alcohol-induced liver disease.
Cirrhosis is the eleventh leading cause of death in the United States. It is
estimated that approximately 50 percent of all deaths due to cirrhosis involve
alcohol abuse and alcoholism.  Alcoholic liver disease encompasses a spectrum
of liver pathology that progresses from steatohepatitis to cirrhosis and
hepatocellular carcinoma.  Cirrhosis is the end stage liver disease developing
from long term hepatic fibrogenesis.  Hepatic fibrogenesis is a process where
excessive deposition of extracellular matrix components, especially collagen,
occurs due to an imbalance between the amount of matrix macromolecules
produced versus degraded in the liver.  Considerable evidence implicates
hepatic stellate cells (HSC) as the primary source of excessive extracellular
matrix in liver fibrosis.  A major feature of fibrosis is the activation of
HSC, consisting of an early initiation phase followed by a perpetuation phase.
Upon activation, HSC undergo transformation and mediate microenvironmental
changes in the liver that include the loss of vitamin A, acquisition of
contractility, perisinusoidal matrix degradation, cellular migration and
proliferation and increased matrix production and accumulation.  Understanding
the developmental, molecular, biochemical and microenvironmental changes that
occur in the hepatic macromolecular extracellular matrix and cellular
constituents of the liver resulting in the pathological sequelae of hepatic
fibrosis are fundamental to design strategies for the prevention and treatment
of the disease.


The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas. This PA, Mechanisms of Alcohol-Induced
Hepatic Fibrosis, is related to the priority areas of alcohol-associated
medical disorders. Potential applicants may obtain a copy of "Healthy People
2000" at http://www.crisny.org/health/us/health7.html.


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. Foreign institutions are not eligible to
apply for Small Grant (R03) awards.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as 
principal investigators.


This PA will use the National Institutes of Health (NIH) individual research
project grant (R01) and the NIAAA Small Grant (R03) Program mechanisms.
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.  The total project period for an
R01 application submitted in response to this PA may not exceed 5 years.

The NIAAA Small Grants (R03) are for no longer than 2 years and no more than
$50,000 direct costs per year.

The NIAAA Small Grant (R03) Program has specific application formats and
review criteria.  Applicants are strongly encouraged to consult with program
staff listed under INQUIRIES to obtain the program announcement for the NIAAA
Small Grant Program (PAR-99-098).  The applicant may also obtain the program 
announcement on the NIAAA home page at http://www.niaaa.nih.gov.

Specific 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


BACKGROUND:  Areas of Interest

The major objective of this Program Announcement is to solicit both basic and
pre-clinical research applications that address the developmental progression
of alcoholic liver disease from steatohepatitis to cirrhosis and
hepatocellular carcinoma with a specific emphasis on stellate cells and their
activation. Basic studies that develop new animal models of liver disease
relevant to disease progression or utilize current animal models to elucidate
cellular, molecular or microenvironmental changes related to disease
progression in alcoholic liver disease are encouraged. Pre-clinical studies
that provide novel insights or propose new hypotheses related to human
alcoholic liver disease are sought.

Examples of focused areas of research include, but are not limited to the

Vitamin A:  Vitamin A (retinol) and its metabolite retinoic acid play an
important role in the regulation of cell proliferation and cell
differentiation.  The activation of HSC is associated with the loss of
cellular content of vitamin A.  On the other hand, treatment with retinoids
suppress HSC proliferation, decrease gene expression of collagen as well as
TGF-beta and thereby attenuate liver fibrosis.  These findings suggest an
inhibitory effect of vitamin A on HSC activation and associated liver
fibrosis.  However, the underlying molecular and biochemical mechanisms of
this effect of vitamin A are not clear.  In the bile duct ligation model of
hepatic fibrosis, increased mRNA levels of procollagen alpha-1(I) and TGF-beta
were associated with diminished retinoic acid signaling in HSC as shown by
decreased mRNA levels of retinoic acid receptor-beta, retinoid X receptor, and
cellular retinol binding protein.  Whether diminished retinoic acid signaling
is causally related to increased collagen production needs investigation.
Also, whether a similar mechanism exists in alcohol-induced hepatic fibrosis
model remains to be determined.  A central question in this line of research
is:  Can vitamin A prevent or down-regulate HSC activation and by what

Acetaldehyde: Acetaldehyde, an immediate metabolite of ethanol, has been
implicated in the development of hepatic fibrosis by increased collagen
production.  Acetaldehyde is primarily produced in hepatocytes and can diffuse
out to interstitial space and affect HSC. Indeed it has been shown to increase
collagen production by cultured rat HSC in vitro by increasing the
transcription of alpha-1(I) collagen gene. At the same time, acetaldehyde
decreased the synthesis of matrix metalloproteinases-1, an enzyme known to
degrade type I collagen, thus promoting the accumulation of collagen in the
liver. Acetaldehyde also increases the expression of other extracellular
matrix components, including type III collagen and fibronectin. Acetaldehyde
increased cell membrane-associated PKC activity of HSC, whereas PKC inhibitors
blocked acetaldehyde-mediated alpha-1(I) collagen gene up regulation,
suggesting a role of this kinase in transducing the intracellular signal.
However, subsequent steps involved in the signal transduction pathways are not
clear. Furthermore, the molecular mechanisms whereby acetaldehyde up-regulates
the transcription of genes for collagen and other matrix proteins are not well
understood. Salient questions that can be addressed are: Does acetaldehyde
initiate or perpetuate HSC activation? What are the biological mechanisms that
mediate acetaldehyde regulation of extracellular matrix deposition? Do
exogenous factors or genetic expression predispose HSC to activation by

Lipid Peroxidation: Chronic alcohol ingestion is associated with oxidative
stress as reflected by increased hepatic levels of lipid peroxidation products
such as malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). MDA and 4-HNE
have been implicated in hepatic fibrogenesis in the intragastric ethanol
infusion model of liver fibrosis and in the bile duct ligation model of liver
fibrosis.  Furthermore, lipid peroxidation products have been shown to induce
gene expression of procollagen alpha-1(I) and increase collagen production by
several folds in cultured HSC. However, other investigators have found a
minimal and only transient effect of lipid peroxidation products. Studies are
required to clarify whether lipid peroxidation products can activate quiescent
HSC to produce increased collagen and identify the molecular and signal
transduction pathways involved.

Iron: Iron is known to play a key role in the development of hepatic fibrosis
probably via oxidant stress and lipid peroxidation. Iron has been shown to
exacerbate the effects of alcohol on liver disease. In intragastric infusion
model of alcoholic liver disease (ALD), supplementation of carbonyl iron (0.25
percent) advanced perivenular fibrosis to bridging fibrosis and cirrhosis.
This potentiating effect was associated with increased lipid peroxidation
which may be an initial step by which excess iron induces fibrosis. The
dietary iron supplementation was also associated with increased NF-kB
activation, up regulation of NF-kB responsive proinflammatory genes such as
TNF, and MIP-1, and mononuclear inflammation which has been implicated in
initiating fibrogenesis. In this model of ALD, even without iron supplement,
hepatic macrophages showed increases in iron content, NF-kB activation, and
TNF and MIP-1 mRNA expression.  All of these effects were abrogated by ex vivo
treatment of the cells with an iron chelator, deferiprone, suggesting the role
of iron in NF-kB activation and associated inflammatory cascade. Thus, iron
may activate HSC via NF-kB activation and inflammation. Investigations are
sought to determine iron absorption and transport in individuals with ALD. 
Studies are required to determine the mechanism(s) by which chronic ethanol
intake sequesters iron in the macrophages. Can iron chelator therapy attenuate
alcohol-induced liver fibrosis?

Cytokines: Alcohol ingestion is known to stimulate production of a myriad of
cytokines from hepatic cells, which have been implicated in the different
stages of ALD through activation of HSC. Cytokines implicated in the loss of
vitamin A by HSC are TNF and PDGF; matrix degradation can be mediated by TNF
and IL-1; cellular migration may be mediated by PDGF; cell proliferation
cytokine are PDGF, TGF-alpha, IL-1, and TNF; matrix accumulation cytokines are
TGF-beta, IL-6, and TNF. Studies are needed to understand the molecular
mechanisms by which these cytokines stimulate the different stages of
fibrogenesis. Do these cytokines act independently or interact with each other
before eliciting their effect on HSC? Are these cytokines released in latent
forms that require activation before affecting HSC? TGF-beta is a major
cytokine implicated in liver fibrogenesis by increasing matrix production.
TGF-beta can indirectly enhance HSC proliferation by increasing the expression
of PDGF. In addition, TGF-beta can enhance autocrine production in HSC. Thus,
once TGF-beta is secreted, it can perpetuate both HSC proliferation and
increased matrix production. It is not clear what mechanism(s)  induces TGF-
beta production by alcohol ingestion. One possibility is through increased
lipid peroxidation and NF-kB activation.

Leukocytes: Alcohol-induced hepatic fibrosis is generally preceded by
inflammation that is associated with parenchymal infiltration of leukocytes
(neutrophils and lymphocytes), which may activate HSC in a paracrine manner.
Studies are needed to understand the role of leukocytes on HSC activation and
subsequent accumulation of extracellular matrix. Increased release of reactive
oxygen species and associated lipid peroxidation appears to be a primary
mechanism by which neutrophils can stimulate increased collagen production by
HSC. Neutrophils can also release proteases, which can digest laminin, an
extracellular matrix protein, which helps maintain HSC in a quiescent state.
Whether these cells can release cytokines in appreciable amounts capable of
HSC activation remains to be investigated. It is also unclear whether these
cells act upon HSC directly as well as through hepatocytes. The role of
lymphocytes in HSC activation is variable depending upon the type of cytokine
secreting-helper T cells. While TH2 cytokine secreting cells may promote
fibrogenesis via the secretion of TGF-beta and IL-4, TH1 secreting cells may
inhibit fibrogenesis through the secretion of gamma interferon. Studies are
required to determine whether gene activation of cytokines and matrix
molecules (e.g., chemokines, adhesion molecules) mediate cellular infiltration
and thereby modulate fibrogenesis.

Intracellular Signaling Pathways: Increasing evidence suggests that mediators
activating HSC such as cytokines, acetaldehyde, and lipid peroxidation
products utilize or initiate intracellular signaling pathways. The following
signaling pathways have been identified in activated HSC: mitogen-activated
protein (MAP) kinase, protein kinase C (PKC), phosphotidylinositol (PI) 3-
kinase, and focal adhesion kinase (FAK). The MAP kinase family has two
important members: the extracellular signal-regulated kinase (ERK) and c-jun
terminal kinase (JNK). PI-3kinase and ERK are involved in PDGF-mediated HSC
proliferation. Activities of ERK and JNK are increased by fibronectin and TNF
during HSC activation. Activation of these cell signaling pathways and their
resultant modification of cellular function in ALD could be the basis for
therapeutic interventions. For example, treatment of rat HSC with a selective
PKC inhibitor significantly suppressed alpha smooth muscle actin expression
and cell proliferation. Could such an inhibitor be utilized in ALD?

Transcription Factors: Several transcription factors are involved in the gene
expression of matrix molecules produced by activated HSC during hepatic
fibrogenesis. The factors implicated in the transcription of collagen genes
are Sp1, Sp3, Zf9, NF-I, USF1, USF2, and NF-kB.  Some of these factors such as
Sp1, Sp3, and NF-kB are also involved in gene expression of biglycans, which
are proteoglycan extracellular matrix proteins. Transcription factors
implicated in HSC proliferation are AP-1 and c-myb. Studies are required to
understand the molecular mechanisms and environment of gene expression as
related to fibrogenesis and ALD. Identification and characterization of gene
regulatory pathways involved in the initiation of HSC activation and
extracellular matrix deposition could have application to novel therapeutic
approaches such as gene therapy.

Matrix Metalloproteinases (MMPs) and their Tissue Inhibitors (TIMPs): Excess
collagen deposition in the liver results from an imbalance between the amount
of collagen produced and the amount degraded by MMPs, a family of proteolytic
enzymes with diverse specificity for different extracellular matrix
components. Limited information is known regarding gene regulation and
expression of the MMPs.  HSC are known to express MMPs that degrade type I and
IV collagens. In individuals with ALD, liver collagenase activity was shown to
be increased at early stages of the disease, but was decreased or absent in
advanced cirrhosis. This may, in part, be responsible for the initial
perisinusoidal matrix degradation that is followed by excess collagen
accumulation in hepatic fibrosis. Studies are required to understand the
physiology of MMP induction and pathology induced by aberrant production.
Investigation of the mechanism(s) that control the genetic expression of these
enzymes and their enzymatic activity are needed. This includes a study of
increased levels of TIMPs that can result in excess accumulation of
extracellular matrix proteins by inhibiting the activities of MMPs. In fact,
increased expression of mRNA for TIMP-1 and TIMP-2 and increased synthesis of
associated proteins have been shown in cultured activated HSC. Similar results
have been shown in animal models of liver fibrosis and in human liver disease.
TIMP-1 levels are also increased in ALD where the cellular source is activated
HSC. Furthermore, in ALD patients, the levels of TIMP-1 correlate with the
severity of the disease. Studies are needed on expression of various TIMPs in
ALD in its various clinical forms and stages. Also the mechanisms by which
alcohol increases TIMP-1 expression need to be elucidated.  This could be a
direct effect of alcohol or mediated through acetaldehyde, alcohol-induced
oxidant stress, or cytokine activation.  Therapeutic Interventions: Basic and
pre-clinical research applications are encouraged to develop therapeutic
interventions for the treatment and prevention of alcohol-induced liver
disease. A particular focus is on the inhibition of progression of liver
fibrosis to cirrhosis and associated hepatocellular carcinoma. In this regard,
some progress has been made by administering polyunsaturated lecithin and its
active components. For example, in baboons, administration of
polyenylphosphatidylcholine (PPC) prevented alcohol-induced septal fibrosis
and cirrhosis which was associated with decreased number of activated HSC.
This effect of PPC was mediated through decreased oxidant stress and increased
collagen breakdown via increased collagenase activity. The uses of
antioxidants such as vitamin A, vitamin E and S-adenyl methionine (SAM), a
precursor of glutathione, have yielded mixed results. Further studies are
needed to investigate candidate molecules related to oxidant stress and
fibrosis and their administration or delivery system (e.g., liposomes, viral
vector) as well as targeted cell type(s). Additionally, anticytokine agents
such as TGF-beta and PDGF antibodies, soluble receptors, and antisense
oligonucleotides need to be experimentally investigated in animal models of
alcoholic liver disease to produce new paradigms for therapy.


It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28,
1994, (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol.
23, No. 11, March 18, 1994, available on the web at the following URL address: 


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://www.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.


Applicants are strongly encouraged to contact the program contacts listed
under INQUIRIES with any questions regarding their proposed project.

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted on the standard receipt dates indicated in the
application kit.  Application kits 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. Applications are also available on the World Wide Web at:

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.


o  FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments) 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.

of the PHS 398. It is not required and will not be accepted with 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 - Use a Modular Grant Budget Narrative page.
(See http://www.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.

o  Under Personnel list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided.

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. The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.

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:

- 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. It is important to identify all exclusions that
were used in the calculation of the F&A costs for the initial budget period
and all future budget years.

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.

Applications not conforming to these guidelines will be considered
unresponsive to this PA and will be returned without further review.

Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute program staff before submitting the application, i.e., as plans for
the study are being developed. Furthermore, the applicant must obtain
agreement from the staff that the Institute will accept the application for
consideration for award. Finally, the applicant must identify, in a cover
letter sent with the application, the staff member and Institute who agreed to
accept assignment of the application.

The title and number of the program announcement must be typed on line 2 of
the face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and five signed photocopies in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


Applications will be assigned on the basis of established PHS referral
guidelines. Applications that are complete will be evaluated for scientific
and technical merit by an appropriate peer review group convened in accordance
with the standard NIH peer review procedures. 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 applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council or board, when applicable.


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 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?

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

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.


Applications will compete for available funds with all other approved
applications. The following will be considered in making funding decisions: 
quality of the proposed project as determined by peer review, availability of
funds, and program priorities.


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

Direct inquiries regarding programmatic issues to:

Vishnudutt Purohit, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-2689
FAX:  (301) 594-0673
Email:  vpurohit@willco.niaaa.nih.gov

Leslie Isaki, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 594-6228
FAX:  (301) 594-0673
Email: lisaki@willco.niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC 7003
Bethesda, MD  20892-7003
Telephone: (301) 443-0915
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov


This program is described in the Catalog of Federal Domestic Assistance No.
93.273. Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC
241, 285, and 290) and administered under NIH grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74 or Part 92, as appropriate. This
program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review. Awards will be
administered under PHS grants policy as stated in the NIH Grants Policy
Statement (October 1, 1998).

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, and 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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