The overall objective of this research is to elucidate the molecular mechanism(s) by which estrogen mediates vascular lesion formation. Occlusive vascular lesions are characterized pathologically by endothelial cell hyperplasia and aberrant smooth muscle cell growth. Estrogen therapy is associated with a worsening of atherosclerosis. Until now adverse estrogenic effects have been explained by the dysregulation of the estrogen receptor (ER). Although the ER is required for the growth of cells, we consider ER actions as a late event when compared to the rapid formation of estrogen-induced oxidants that initiates the early signal for cell growth. We have shown that estrogen-induced oxidants signal endothelial cell proliferation and blood vessel formation. Since pathogenic blood vasculature formation contributes to the etiology of vascular disease, we postulate that exposure to estrogen therapy is harmful to the human cardiovascular system. This revised proposal will examine the role by which 172-estradiol (E2) activates a redox sensitive Pyk2 signaling pathway involved in the pathology of vascular lesions. Therefore, the objective of this proposal is to elucidate the molecular mechanism by which estrogen induces vascular lesion formation. The hypothesis of this proposal is that a Pyk2/GPR30/Vav1 complex mediates pathogenic blood vasculature formation in response to exposure to estrogen. We have formulated the following inter-related, focused specific aims to test our hypothesis:
Aim 1 : To determine whether estrogen exposure initiates Pyk2 protein-protein interactions resulting in a Pyk2/GPR30/Vav1 complex.
Aim 2 : To determine the mechanism by which estrogen-induced Pyk2 protein- protein interactions signal Id3 to block p21Cip1 expression. The long-term goal of this research project is to determine whether in vivo estrogen-induced Pyk2 signaling controls pathogenic blood vasculature formation. However, this long-term goal is not the purpose of this SC3 grant proposal;rather we intend to generate preliminary data from this SC3 Award that will be used to apply for successful NIH R01 funding in which we will include the determination of in vivo whether estrogen-induced Pyk2 signaling controls the formation of human vasculature in a mouse model. The PI's career goal is to become an independent investigator in the field of cardiovascular toxicology. The PI plans to achieve this objective by investigating the molecular mechanism by which estrogen induces vascular lesion formation. Florida International University offers a rich academic environment and well-respected research infrastructure that will provide a supportive setting to foster the PI's career development. The findings from the proposed research will contribute to a more profound understanding of how estrogen therapy mediates the formation of occlusive vascular lesions. This, in turn, will give new insights into the mechanisms by which estrogen increases the risk of occlusive vascular lesions and will identify novel targets for the treatment of vascular lesions in individuals exposed to these compounds.

Public Health Relevance

There is now increasing evidence that exposure to estrogen therapy may contribute to the development of cardiovascular disease. This revised proposal will examine the mechanism by which estrogen signals Pyk2 protein-protein interactions to produce pathogenic vascular lesions. The results obtained will give new insights for the molecular mechanism of estrogen-induced vascular lesions. And it will identify novel targets of treatment for pharmaceutical estrogen-induced vascular lesions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
1SC3GM084827-01A1
Application #
7762127
Study Section
Special Emphasis Panel (ZGM1-MBRS-7 (GC))
Program Officer
Okita, Richard T
Project Start
2010-01-01
Project End
2013-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
1
Fiscal Year
2010
Total Cost
$108,375
Indirect Cost
Name
Florida International University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199