VASCULAR AND HEMATOPOIETIC DEVELOPMENT AND DISEASE

Release Date:  March 6, 1998

PA NUMBER:  PA-98-035

P.T.

National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

This initiative is focused on the definition of critical processes that direct
differentiation and organization of the vascular system with specific emphasis
on factors that specify the diverse phenotypes of endothelial, blood, and
vascular smooth muscle cells.  It encourages innovative approaches to identify
and characterize precursor cells, studies to elucidate the regulatory mechanisms
which determine and maintain the diverse phenotypes, and strategies to define how
these developmental mechanisms might be involved in pathological conditions of
the mature animal.  The ultimate goal is to provide the foundation for new
therapies to treat cardiovascular, lung and blood diseases based on morphogenetic
principles.

HEALTHY PEOPLE 2000

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, Vascular and Hematopoietic
Development and Disease, is related to the priority areas of maternal and infant
health, heart disease and stroke and, diabetes and chronic disabling conditions. 
Potential applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-512-1800).

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 or local governments, and eligible agencies of the
federal government.  Awards in response to this PA will be made to foreign
institutions only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to apply.

MECHANISM OF SUPPORT

The mechanisms of support will be the National Institutes of Health (NIH)
research project grants (R01).  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.

RESEARCH OBJECTIVES

Background

Vascular anomalies, disease, or remodeling occur in many congenital and acquired
diseases such as cardiovascular malformations, diabetes, hypertension, pulmonary
diseases of arteries and veins, peripheral vascular disease and myocardial
ischemia and infarction.  Defects in vascular development have been identified
as a major cause of in utero fetal demise.   Yet, there is a paucity of knowledge
regarding the embryonic cells that are progenitors of endothelial and vascular
smooth muscle cells and the factors that determine their commitment to a blood
vessel phenotype.   Little is known of mechanisms which establish phenotypic
variability in vascular beds and how these mechanisms might function in
maintenance of a healthy vascular system.

In children with complex congenital heart diseases that result in abnormal
pulmonary flow, such as tetralogy of Fallot, there is abnormal development of the
pulmonary vasculature.   Medical and surgical management could be enhanced if
pulmonary vascular remodeling could be induced.   Cardiac transplantation is
often followed by accelerated atherosclerosis, which may be due to up regulation
of factors that stimulate endothelial cell activation.  The hallmark of the
restenosis following percutaneous transluminal coronary angioplasty or coronary
atherectomy is the abnormal growth and migration of putative vascular smooth
muscle cells.  These examples illustrate the potential benefits of elucidating
the mechanisms of endothelial and smooth muscle cell regulation as a first step
toward clinical application.  This has already been accomplished for rare
vascular diseases such as hereditary hemorrhagic telangiectasia (Rendu-Osler-
Weber syndrome), ataxia-telangiectasia, and venous malformation where gene
mutations have been identified through fundamental research and directly
correlated to genetic vascular disorders in humans.

One of the central problems in hematology relates to the origin and development
of pluripotential hematopoietic stem cells.  How these cells arise and what
factors are required for their proliferation in an undifferentiated state are
poorly understood. Understanding the mechanisms that govern the development of
hematopoietic stem cells will significantly contribute to our ability to use stem
cells of any source (fetal, neonatal, or adult) therapeutically in a variety of
clinical transplant settings.  The findings will provide new approaches to
manipulate these populations resulting in more effective hematopoietic stem cell
transplantation therapies to treat thousands of adults and children with life-
threatening hematologic diseases.  In addition, the prospects for gene therapy
will be immeasurably enhanced.

In the lung, developmental studies have largely focused on commitment and
differentiation of the pulmonary epithelium during organogenesis.  However, an
understanding of the relationship between vasculogenesis and the generation of
normal organ structure may provide further insight into developmental aberrancies
such as lung hypoplasia and bronchopulmonary dysplasia.  Clarification of the
factors determining vasculogenesis and angiogenesis in the lung may result in new
approaches to the treatment of pulmonary hypertension, acute lung injury and
chronic lung disease.

It has become clear that both endothelial and hematopoietic cells are derived
from a restricted precursor or stem cell population and some evidence exists to
suggest that endothelial and blood cells are derived from a common precursor cell
or hemangioblast.  However, the mechanisms by which the endothelial and blood
cell populations subsequently develop further diversity remain, for the most
part, to be discovered.  Knowledge to date suggests that at least some of these
mechanisms are important for the maintenance of healthy blood and vascular
systems and for repair of damage in the mature organism.  Thus, defining the
mechanisms that regulate differentiation of this population of stem cells could
lead to new therapeutic modalities for the treatment of congenital and acquired
blood and blood vessel diseases including those related to the pulmonary and
cardiac circulations, as well as the peripheral and lymphatic circulations.

Endothelial cells derived from stem cells in the yolk sac blood islands and
embryo proliferate, migrate, differentiate and organize into a  vascular plexus
(vasculogenesis) that forms the foundation for the early vascular system.  This
system then grows by budding (angiogenesis) and by recruiting vascular smooth
muscle cells and other components of the mature vessel wall.  Relatively little
information is available about the mechanisms that regulate early vascular
remodeling and the development of endothelial cell diversity in various vascular
beds so that they display a morphologic organization that is characteristic of
the context of the surrounding tissue.  In this regard, selectivity of gene
expression is an important area requiring study.  Identification and
characterization of unique endothelial transcription factors are essential for
the development of therapeutic strategies for directing endothelial specific gene
expression.  Furthermore, very little is known about the mechanisms by which
pericytes and vascular smooth muscle cells are recruited from mesenchymal and
neural crest cells.  It is thought that smooth muscle cell differentiation and
proximal organization around developing vessels are essential components in
determining vessel viability, lumen size and wall strength.  Yet, little is known
about these critical processes.

New insights regarding the intimate relationship between hematopoietic and
vascular development are emerging.  The cells' spatial association and sharing
of certain antigenic determinants, including Flk-1, Tie-2 and CD34 strengthen
this putative association.  Recently, cells that were isolated from peripheral
blood were shown to express CD34 or Flk-1 and to differentiate into endothelial
cells in vitro, again suggestive of a common precursor.  Further elucidation of
the shared antigenic determinants role in these processes will enhance our
understanding of both hematopoietic and vascular developmental processes.  A
number of vascular specific growth factors and their receptors have been shown
to play unique roles at critical stages in endothelial development, vessel
formation and hematopoiesis.  However, the signal transduction cascades and
transcriptional regulation that mediate the effects of these growth factor-
receptor interactions have not been identified.

Another goal of this program is the identification of inducers of hematopoiesis
and/or the hematopoietic stem cell in the early embryo and  fetus.  The growth
factors that induce blood formation are poorly understood.  The molecules that
initiate commitment of the putative hemangioblast to a hematopoietic fate have
not been identified.  Characterization of factors involved in mediating the
differentiation of hematopoietic cells from an early stem cell would provide a
major advance in our understanding of a critical step in hematopoiesis. 
Extensive work is ongoing in the area of signaling pathways of hematopoietic
growth factor receptors but few data exist on how signals from these receptors
influence the function of lineage-restricted transcription factors.  Thus,
studies seeking to characterize the molecular interactions between these
components are important for relating the programs activated by growth factors
to hematopoietic development and will help unravel the interplay between these
important processes.

Emphasis will be also placed on pulmonary vascular development, which continues
postnatally, and is thought initially to involve both vasculogenic
differentiation of endothelial cells from gut mesoderm and angiogenic extension
of the six pharyngeal arches to form portions of the pulmonary arteries. 
Extensive endothelial diversity develops (from large muscular arteries to
capillary endothelia) from a restricted stem cell population.  Although
considerable research has been devoted to the mechanisms regulating cell-specific
expression in the pulmonary epithelium, similar knowledge is lacking for the
pulmonary endothelium.  Recent attempts at viral mediated gene therapy have shown
that, unlike the endothelial cells of the systemic circulation, pulmonary
endothelia are particularly susceptible to inflammation.  This highlights the
unique nature of the pulmonary vascular bed and suggests alternative approaches
might be required for effective gene transfer.  In addition, pulmonary
development may be influenced by small alterations in blood flow since congenital
heart diseases that affect pulmonary vascular flow often result in abnormal
development of the pulmonary vascular bed.  While shear stress has been shown to
affect endothelial gene expression in some vessels, its role in pulmonary
vascular development has not been evaluated.  Clearly a better understanding of
the interplay between intrinsic or cell autonomous gene expression and
flow-mediated alterations may help direct therapies to enhance pulmonary growth. 
In addition, knowledge of factors that determine the differentiation of
endothelial beds with low resistance characteristics of the pulmonary artery
could result in new approaches to treatment of pulmonary hypertension in the
newborn and in the adult.

Critical Areas of Research Opportunity

The goal of this program is to foster research that will provide new insights
into the earliest steps in blood and vessel formation and allow investigation of
the fundamental processes of commitment and diversification during development. 
One of the major goals of this program is to develop novel approaches to the
lineage relationships and genetic pathways determining endothelial and
hematopoietic progenitors.  In addition it is designed to encourage studies that
focus on the mechanisms by which these developmental processes are recapitulated
during pathological processes in the mature animal.  This knowledge can then be
exploited to design new therapeutic strategies.  Specifically, this program will
focus on the role of discovery of genes responsible for the initiation of stem
cell differentiation and subsequent diversification of endothelial, blood, and
vascular smooth muscle cell phenotypes, including growth factors, signal
transduction molecules and cascades, and cell type-specific transcriptional
regulation.  The following examples are given for illustrative purposes only.  
Investigators are encouraged  to develop their own innovative ideas to address
the goals of the PA.

o  Development of novel approaches to the identification, isolation, and
characterization of the hemangioblast and pulmonary and cardiovascular
endothelial precursor cells

o  Identification and characterization of novel inducers that regulate stem cell
self-renewal, proliferation, and differentiation in the early embryo and  fetus

o  Delineation of genes or transcription factors which determine the commitment
of progenitor cells to endothelial or hematopoietic cell lineage

o  Identification and characterization of factors determining endothelial
diversity and organ specific vascularization patterns

o  Elucidation of the origins, lineage and genetic determinants of endothelial
and vascular smooth muscle cell development in  the lung and cardiovascular
system

o  Define the unique parameters that determine and direct pulmonary vascular
development

o  Identification of mutations which perturb normal vessel assembly and
remodeling in model species

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
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 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 of
March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the program staff or
contact person listed below. Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Investigators who are considering preparing an application in response to this
program announcement are invited, but not required, to discuss their project with
NHLBI and NIDDK staff listed under INQUIRIES in advance of formal submission. 
Specific information on research training and career development mechanisms and
eligibility may also be accessed at the following address on the NIH Home Page
on the world wide web: http://www.nih.gov/grants/training/careerdev/RTCDINTRO.HTM

Applications for R01 grants are to be submitted on the research grant application
form PHS 398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Applications kits are available
at most institutional offices of sponsored research and may be obtained 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:  ASKNIH@od.nih.gov.

To identify the application as a response to the PA, check "YES" on Item 2 of
page 1 of the application and enter the title and PA number: VASCULAR AND
HEMATOPOIETIC DEVELOPMENT AND DISEASE, PA-98-035.

Send or deliver the completed application and five signed, exact photocopies of
it to:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health Service
referral guidelines.  Applications will be reviewed for scientific and technical
merit in accordance with the standard NIH peer review procedures.  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.

Review Criteria

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 this 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  (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 for institutional support?

AWARD CRITERIA

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 priority.

INQUIRIES

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

Inquiries regarding programmatic issues may be directed to:

Dr. Lan-Hsiang Wang
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 9044, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0510
FAX:  (301) 480-1335
Email:  lw72f@nih.gov

Dr. Helena Mishoe
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10156
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 480-0868
Email:  hm31y@nih.gov

Dr.  Mary Ann Berberich
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
Email:  bererim@gwgate.nhlbi.nih.gov

Dr. David G. Badman
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13C, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  David_Badman@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. William Darby
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7128, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  DARBYW@GWGATE.NHLBI.NIH.GOV

Aretina Perry-Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
Email:  PerryA@ep.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.839 and 93.849.  Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC 241) and administered under PHS grant policies
and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. 
This program is not subject to the intergovernmental review requirements of
Executive Order 12372, or to 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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