Grant: $256,075 - National Institutes of Health - Jul. 16, 2009
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Award Description: Cardiovascular disease is the leading cause of death for both men and women in the United States and the world. There is a profound pattern in the time of day at which the death occurs. It is in the morning, when the endothelium is most vulnerable and blood pressure surges, that stroke and heart attack most frequently happen. Thus, there exists a pattern of timing in cardiovascular biology and disease. The molecular mechanism that underlies biological timing – the circadian clock – is expressed throughout the body, including blood vessels. We have found that blood vessels exhibit 24-hour oscillations in the central components of the circadian clock: Bmal1, Clock, Period, and Cryptochrome genes. Moreover, these proteins are expressed within the endothelium, ideally positioned to modify endothelial signaling and vascular function. The central hypothesis of this application is that the circadian clock has a local function within the vasculature to influence endothelial signaling and vascular remodeling. In the parent application, we proposed to study vascular remodeling and signaling in Bmal1-knockout (KO) and Clock mutant (mut) mice. In this Supplemental Application, we propose to extend our studies of the Parent grant (following the same Aims), by using newly attained models of circadian gene mutation in our laboratory-the Per1/Per2/Per3 triple knockout mice (TKO) and Clock-KO mice. Per-TKO mice lack central and peripheral locomotor rhythms when acclimated to constant darkness and have a slow clock in standard light dark conditions. In contrast to Bmal1 and Clock, the Per-TKO are negative limb mutants. This is important as there are examples where negative limb mutants have different phenotypes from positive limb mutants despite changes in rhythmicity. Clock-KO mice, which are distinct from the Clock mut mice, lose rhythms in periphery, not in locomotor or central activity. Thus, this supplement will provide significant insight into the role of distinct circadian clock components and circadian rhythms per se, in the progression of vascular disease.
Project Description: As defined in the Award Description field.
Jobs Summary: A Post Doctoral Fellow works on this project, employed by the prime recipient. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 16, 2009. Help expand these official descriptions using the wiki below.