R01HL157626

Retinoic Acid Induced Lymphangiogenesis for Post-Surgical Lymphedema

Lymphedema is an incurable condition characterized by lymphatic obstruction, tissue swelling, immune dysfunction, and fibrosis after lymphatic injury. It affects 5 million Americans and is associated with poor quality of life due to extremity disability, disfigurement, and the risk for recurrent limb-threatening infection. In the US, lymphedema is most commonly a consequence of lymph node dissection for the treatment of solid tumors such as breast or pelvic cancer. Despite its common occurrence and morbidity, there are currently no effective drug treatments available.

Using preclinical rodent models of lymphedema, we have shown that 9-cis retinoic acid (RA) significantly accelerates lymphatic regeneration following injury, restores functional lymphatic drainage, and prevents the development of lymphedema. Our overarching hypothesis is that RA-mediated lymphangiogenesis is a promising therapy for secondary lymphedema. The objective of this proposal, which is the first logical step towards implementing this treatment clinically, is to increase our understanding of the mechanisms by which RA regulates lymphangiogenesis and develop a translational framework for the use of these compounds.

The specific aims of this proposal include:

Aim 1: Determine how RA selectively induces lymphangiogenesis.
Aim 2: Elucidate the roles of FGFR and VEGFR signaling in RA-mediated lymphangiogenesis.
Aim 3: Use early biomarkers of lymphatic insufficiency to develop a predictive model that can guide the initiation of RA therapy.

Based on the current lack of effective therapy, it is clear that there is a need to develop an etiology-focused treatment for post-surgical lymphedema. The proposed studies will address important mechanistic questions regarding RA-mediated lymphangiogenesis and also develop an early biomarker-based predictive model that will guide treatment windows for RA therapy. The proposed work will significantly improve our understanding of RA-mediated lymphangiogenesis as well as support the clinical translation of RA as a preventative treatment regimen for post-surgical lymphedema.

Rutgers The State University Of New Jersey

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Newark, New Jersey 071073001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 406% from $631,277 to $3,193,446.