Administrative Supplement to Award "Circadian regulation of vascular aging"

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Abstract: Aging is the major risk factor for a variety of diseases, particularly Alzheimer's dementia (AD) and cardiovascular diseases. Vascular contribution to cognitive impairment and dementia (VCID) is the second most common cause of dementia after AD. Vascular damage in the mid-brain regions causes progressive cognitive impairment similar to that of AD; and vascular dementia often coexists with Alzheimer's plaques. Therefore, better understanding of VCID may provide new solutions that improve prevention and management of VCID and AD. Cerebrovascular dysfunction, featuring brain vascular lesions and infarctions, limits blood flow and reduces oxygen and nutrient supply to the brain which results in impairment of brain activity and cognitive function. Vascular aging not only impairs normal vascular contraction and compliance but also increases the incidence of cardiovascular disease, including hypertension, stroke and peripheral artery disease. Clinical, epidemiological and experimental studies have demonstrated that multiple vascular diseases, such as stroke, hypertension, atherosclerosis and arterial stiffness, are associated with VCID and accelerate the progression of cognitive impairment and dementia. Our current NHLBI-funded Parent proposal on “Circadian regulator of vascular aging” (5R01HL146103) aims to uncover the previously unknown function of the master osteogenic transcriptional factor, Runx2, in regulating vascular smooth muscle cell (VSMC) function during the development of vascular aging. The Parent proposal focuses on the study of arterial stiffness and calcification in the large aortic arteries; and attempts to define the previously unknown regulation of Runx2 by circadian clock-mediated protein O-GlcNAcylation. Studies in the Parent proposal identified increased Runx2 expression in mouse aortas in an age-dependent manner, which was associated with increased pulse wave velocity (PWV), an indicator for arterial stiffness and a predictor for future cardiovascular events. Preliminary studies determined that Runx2 deficiency in SMC inhibited arterial stiffness, and improved cerebral blood flow. Furthermore, mice with SMC- specific Runx2 deletion took less time in finding objects in the water maze test and moved faster in the open field test, suggesting improved cognitive function. These exciting observations suggest a new role played by Runx2 in SMC in regulating cerebral arterial blood flow and cognitive function. Thus, this Supplement application will take advantage of the two new SMC-specific deletion of BMAL1 (clock dysfunction) and OGT (O-GlcNAcylation ablation) mouse models generated from the Parent R01 to uncover the novel function of the BMAL1/OGT/Runx2 signaling cascade in regulating cerebral vascular function and VCID. Furthermore, we will dissect the distinct and overlapping molecular determinates in two vascular systems, aortic and cerebral, using unbiased system biology approaches, which may lead to identification of new signaling cascades and signature cell populations that uniquely regulate cerebral vascular function and VCID; and provide new insights into novel strategies for prevention of age-related vascular disorders, and improving public health and lifespan.