Distinct pathways of VPF/VEGF receptors

Project: Research project

Project Details


DESCRIPTION (Provided by applicant): Angiogenesis plays a pivotal role in
several important disease processes as well as in normal physiology. It is
widely anticipated that modulation of angiogenesis (inhibition in tumors,
stimulation in vascular insufficiency) will provide important therapeutic
benefit. Many different cytokines and growth factors express angiogenic
activity, of these VEGF-A stands out because of its potency, selectivity for
vascular endothelium, and its consistent over expression in malignant tumors
and in other clinical conditions in which angiogenesis plays an important role.
VEGF-A acts selectively (though not exclusively) on endothelial cells (EC) by
means of two high affinity receptor tyrosine kinases Flt-1(VEGFR-1) and
KDR/Flk-1(VEGFR22) Both of these receptors are expressed at increased levels by
BC during development and in pathophysiological angiogenesis. Since, most of
the endothelial cells express both of the receptors and both of them can
homodimerize upon binding to VEGF-A; therefore it is difficult to comprehend
the molecular function of the individual receptor in the presence of the same
ligand. The proposed study aims to dissect the functional aspects and sole
responsiveness of these receptors for VEGF-A mediated signaling in EC. Chimeric
receptors of both VEGFR-1 and -2 and their respective mutants will be utilized
to study signaling pathways responsible for the individual receptors in
vascular endothelial cells. Aim 1 will focus to reveal the molecular function
and dissect the signaling pathways for proliferation vs. migration channeling
through VEGFR-2. We will also define the receptor(s) responsible for
endothelial cell sprouting and its subsequent signaling pathways. In Aim 2,
investigation of the functional aspects of VEGFR-1 in endothelial cells will be
performed. Furthermore, examination of inhibitory role of the VEGFR-1 for the
VEGFR-2 function(s) and the pathways necessary for the inhibition will also be
demonstrated. In addition, it will be tested whether VEGFR- 1 has any
functional relationship with neuropilin-1, a new VEGF-A receptor of unknown
function, particularly in EC migration. In Aim 3, the data from Aims 1 and 2
will be utilized to evaluate the signaling pathways between normal vs.
tumor-induced angiogenesis. A novel protein delivery system will be utilized or
retroviral mediated genetic manipulation will be carried out to inactivate the
target molecule(s) in normal as well as tumor-induced angiogenesis. By
targeting the same signaling components in normal as well as tumor-induced
angiogenesis, we will get a better picture and make a better comparison between
these two events. The proposed study thus will delineate the individual role of
the receptors in VEGF-A-mediated signaling and will also shed new light on the
molecular mechanisms of angiogenesis. Taken together these experiments are
likely to identify new therapeutic targets in order to combat angiogenesis in
tumors and also in other disease processes.
Effective start/end date4/1/026/30/15


  • Medicine(all)