This Program Announcement expires on December 31, 2003, unless reissued.

PATHOGENESIS AND TREATMENT OF LYMPHEDEMA

Release Date:  December 14, 2000 (see addendum NOT-CA-03-037)

PA NUMBER:  PA-01-035

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov/)
National Institute of Child Health and Human Development
 (http://www.nichd.nih.gov/)
National Institute of Arthritis and Musculoskeletal and Skin Diseases
 (http://www.nih.gov/niams/)
National Cancer Institute
 (http://www.nci.nih.gov/)

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME"  CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO  STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI), National Institute of
Child Health and Human Development (NICHD), National Institute of Arthritis
and Musculoskeletal and Skin Diseases (NIAMS), and the National Cancer
Institute (NCI) invite qualified researchers to submit applications for
research project grants to investigate the pathogenesis and new treatments for
primary and secondary lymphedema.  The purpose of this program announcement is
to stimulate research on the biology of the lymphatic system, and to
characterize at the molecular, cellular, tissue, organ, and intact organism
levels, the pathophysiologic mechanisms that cause the disease, and to
discover new therapeutic interventions.  The scope of this research includes
developmental biology and genetics of the lymphatic system to identify and
characterize genes important for its organization and regulation.  Such
knowledge will help to improve early diagnosis of affected individuals, the
choice and timing of treatment, and genetic counseling.  Research is also
needed on the pathophysiology of the disorders of skin and subcutaneous tissue
secondary to chronic lymphedema, and lymphedema which results from cancers and
cancer treatment, with an ultimate goal to develop more targeted and effective
therapies.
 
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 Program Announcement (PA),
"Pathogenesis and Treatment of Lymphedema" 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 PA will use the National Institutes of Health (NIH) individual research
project grant (R01) award mechanism. The applicant will be solely responsible
for the planning, direction, and execution of the proposed project, which is
not to exceed a period of 5 years.  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
http://grants.nih.gov/grants/funding/modular/modular.htm.

RESEARCH OBJECTIVES

The lymphatic system comprises an important secondary circulatory system,
returning interstitial fluid back to the venous circulation. Prior to this
function, lymphatic vessels also regulate accumulation and turnover of
interstitial fluid. When the mechanisms involved with this regulation become
unbalanced, lymphedema results. There are two major types of lymphedema:
primary (congenital) and secondary (caused by tissue injury, scarring, lymph
node removal, or infection). For primary lymphedema, there is an early onset
form (Milroy's disease) which is relatively rare and presents at birth. A more
common type (Meige's disease) develops during puberty, representing
approximately 80 percent of all cases. A third form, lymphedema tarda, occurs
after the age of 35. Lymphedema frequently presents with one leg being more
swollen than the other, which is not only disfiguring, but can lead to a
severe infection (cellulitis), and diseases of the skin and subcutaneous
tissues.  Primary lymphedema is inherited in an autosomal dominant fashion,
with variable expressivity and penetrance, and with women affected almost
three-fold more often than men.  The complexity of lymphatic development and
function is likely to be regulated by a variety of unidentified genes, which
result in the phenotype secondary to mutations in those genes.  Gene defects
have been mapped in several families, with a recent study showing that a form
of primary lymphedema involves a genetic missense mutation located on
chromosome 5 for the receptor for vascular endothelial growth factor-C. This
genetic lesion may implicate specific tyrosine kinase receptors as causative
in certain types of lymphedema. However, the exact mechanisms which contribute
to  primary lymphedema remain unknown. 

The incidence of primary lymphedema has been estimated to be between 1/6000 to
1/300 live births.  Thus, it could be a rare disease, or a more common disease
which is underrecognized. On the other hand, there are 3-5 million people
affected with secondary lymphedema in the United States, and according to the
World Health Organization as many as 170 million world-wide. The secondary
type of lymphedema develops after tissue injury, especially after cancer
surgery, radiation therapy,  trauma to the lymphatic system and lymphangitis,
inflammation or infection (e.g. filariasis) that interrupts normal lymphatic
pathway function. 
 
Although lymphedema has been recognized for over a century, understanding its 
causes has received limited attention. The etiology of the disease is believed
to be complex, involving defective fluid and solute transport across lymphatic
vessels, insufficient propulsion of lymph within lymphatic vessels, and
developmental defects unique to the lymphatic system. Further, therapy also
has lagged, despite the prevalence of the disease, and little relief is gained
from current interventions. One important factor responsible for the lack of
study and treatment of lymphedemas is the paucity of unique animal models,
including transgenic and knockout models, compared to other diseases. 

In view of the limited attention currently given to the biology of the
lymphatic system, and the treatment of lymphedema, the NHLBI, NICHD, NIAMS,
and NCI are interested in approaches that will identify the developmental,
molecular, and cellular defects that contribute to lymphedema as well as the
development of effective therapeutic interventions to treat both primary and
secondary lymphedemas. Examples of some research topics are listed below to
illustrate the objectives of this program announcement. It is not required
that all or any of these ideas be included; investigators are encouraged to
submit applications that are relevant to the goals of this program
announcement.

1.  Comparative studies of gene expression in lymphedematous and normal
tissues, using techniques such as laser capture microdissection and high
density microarrays to identify molecular targets.

2.  Studies on the phenotypic and genotypic differences of lymphatic vascular
cells, compared to arterial and venous vascular cells.

3.  Elucidation of the process of lymphangiogenesis, including the growth
factors, cytokines, and matrix molecules associated with the formation of
functional lymphatic vessels.  A potential role of trophism to lymph nodes,
and the effect of reimplantation of nodal tissue on lymphedema.
                                                                 
4.  Development of a biophysical model(s) for interstitial fluid exchange
across the lymphatic wall, and the role of the lymphatic matrix in the
development of lymphedema. Characterization of the physical and biological
mechanisms in the propulsion of lymph within lymphatic vessels.

5.  The creation of animal models to confirm the identification of putative
genes contributing to lymphedema, and the development of animal models to
assess new treatments.

6.  The development of methods to image and quantitate lymph flow to provide
useful endpoints for clinical evaluations.

7.  Approaches to explain the asymmetry between more and less affected limbs
in an individual with primary lymphedema, when the genetics and environment
appear to be uniform. Also, the developmental or hormonal basis for delayed
onset during puberty.

8.  Studies on the developmental biology and developmental genetics of the
lymphatic system, i.e., the identification and characterization of genes
important in the organization and regulation of the development of the
lymphatic system.

9.  Studies on diseases of skin and subcutaneous tissue that result from
chronic lymphedema.

10.  Methods to prevent radiation-induced or surgery-related lymphedema

To foster data sharing in addition to presentations and publications,
investigators should consider how to make experimental results available to
other scientists for data mining, and how to make archived data interoperable
with commercially available software.

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.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit. Application 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: [email protected].

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 or Center (IC) program staff before submitting the application, i.e,
as plans for the study are being developed. Furthermore, the application must
obtain agreement from the IC staff that the IC 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 or Center who
agreed to accept assignment of the application. 

This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment. Refer to the NIH Guide
for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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.

Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. (Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS
398 application instructions.) The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for
each year. This is not a Form page.

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

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of all personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount. Include the Letter of
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for all
key personnel, following the instructions below. No more than three pages may
be used for each person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm

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

o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the type
of agreement and the date. All appropriate exclusions must be applied in the
calculation of the F&A costs for the initial budget period and all future
budget years.

o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review. 

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:

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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be evaluated for scientific and technical merit
by an appropriate scientific 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

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
evaluated.

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

o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.

AWARD CRITERIA

Applications will compete for available funds with all other recommended
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 are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome. Direct inquiries regarding programmatic
issues to:

Henry Chang, M.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Telephone: (301) 435-0067
FAX: (301) 480-1060
Email: [email protected]
 
Stephen S. Goldman, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7956
Bethesda, MD 20892-7956
Telephone: (301) 435-0565
FAX: (301) 480-2849
Email: [email protected]

Michael E. Whalin, Ph.D.
Developmental Biology, Genetics and Teratology Branch
National Institute of Child Health and Human Development
Building 6100, Room 4B01
6100 Executive Blvd. MSC 7510
Bethesda MD 20892-7510
Telephone: (301) 496-5541
FAX: (301) 480-0303
Email: [email protected]

Alan N. Moshell, M.D.
Skin Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Building 45, Room 5AS25L
45 Center Drive, MSC 6500
Bethesda, MD 20892-6500
Telephone: (301) 594-5017
FAX: (301) 480-4543
Email: [email protected]

Colette S. Freeman, Ph.D.
National Cancer Institute
Division of Cancer Biology
Executive Plaza North, Room 5000
Bethesda, MD 20892-7950
Telephone: (301) 496-7028
Fax (301) 402-1037
Email: [email protected]

Direct inquiries regarding fiscal matters to:

Suzanne White
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Rockledge 2, Room 7150
Bethesda, MD 20892-7926
Telephone: (301) 435-0171
FAX: (301) 480-3310
Email: [email protected]

Douglas Shawver                                        
Grants Management Branch
National Institute of Child Health and Human Development
Bldg. 6100, Room 8A17F
6100 Executive Blvd. MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 435-6999
FAX: (301) 402-0915
Email: [email protected]

Melinda Nelson
Grants Management Officer
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Building 45, Room 5AS49F
45 Center Drive, MSC 6500
Bethesda, MD 20892-6500
Telephone: (301) 594-3535
FAX: (301) 480-5450
Email: [email protected]

Mr. Bill Wells
Grants Administration Branch
National Cancer Institute
Executive Plaza South 243
Bethesda, MD  20892-7150
Telephone:  (301) 496-8796
Fax:  (301) 496-8601
Email:  [email protected]

AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance
(http://12.46.245.173/pls/portal30/CATALOG.AGY_PROGRAM_LIST_RPT.show) Nos. 93.837 and 93.839 (NHLBI),
93.865 (NICHD), 93.846 (NIAMS), and 93.396 (NCI).  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 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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