2014 — 2017 |
Lyle, Alicia N |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
The Role of Human Osteopontin Isoforms in Collateral Formation
DESCRIPTION (provided by applicant): The development of new collateral blood vessels to provide blood flow to ischemic tissues is an extremely complex process that occurs as a result of several distinct mechanisms including sprouting of new blood vessels from existing vascular structures, migration of bone marrow-derived endothelial precursor cells to sites of ischemia, recruitment of inflammatory cells, and the arterialization of endothelial channels (both existing and newly formed) with vascular smooth muscle cells. While much has been learned about the involvement of growth factors in these processes, the precise molecular mechanisms underlying adaptive vascular growth mediated by other factors, such as inflammatory proteins, are extremely complex and require further investigation. By understanding the underlying mechanisms that drive collateral vessel formation, we can develop new therapeutic approaches to increase functional collateral growth in patients with obstructive arterial disease for which surgery is essentially the only available treatment. We have demonstrated that osteopontin (OPN), an inflammatory cytokine and matricellular protein, is integral to the formation of collateral vessel growth and its expression is significantly upregulated in response to ischemia. However, it has recently become evident that humans express three OPN isoforms (a, b, and c), which are differentially upregulated in various disease settings and may have different functions. There is currently nothing known about how these three OPN isoforms function to influence cell migration and collateral vessel formation in cardiovascular disease. Therefore, this career development proposal was designed to define the functional differences of the human OPN isoforms in the collateral formation process by using a novel and translational approach to deliver these OPN isoforms to ischemic tissues. Our preliminary data strongly support that human osteopontin isoforms differentially regulate collateral vessel formation, smooth muscle cell migration, and cell signaling. We therefore hypothesize that human OPN isoforms exhibit differential effects on collateral formation through divergent effects on the migration of inflammatory cells and vascular smooth muscle cells, necessary for arterialization. The experiments described in this application will dissect how these three human OPN isoforms function to modulate these responses. We propose to make use of osteopontin deficient mice to define the specific role of each human osteopontin isoform in new vessel formation and will test our overall hypothesis by investigating the following specific aims: 1) Define the role of human OPN isoforms on collateral vessel formation in vivo, 2) Investigate the differential effects of human OPN isoforms on vascular smooth muscle cell migration, and 3) Determine the mechanism by which human OPN isoforms mediate differential cell migration.
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