Novel mechanisms of cerebral microhemorrhages in aging
Description: The increasing prevalence of multifocal cerebral microhemorrhages (CMHs, also known as “cerebral microbleeds”) is a significant, newly recognized problem in the aging population. CMHs are responsible for "transient ischemic attacks" (TIAs or "mini-strokes") and contribute to cognitive decline. Clinical studies show that aging and hypertension significantly increase prevalence of CMHs. Although CMHs affect ~ 30 to 50% of older individuals, their pathogenesis remains completely obscure and there are no therapeutic interventions available for prevention. The objective of the present proposal is to elucidate the specific age-related mechanisms that are responsible for increased cerebromicrovascular fragility and identify potential targets for prevention of CMHs using innovative preclinical models. Results from recent studies let us focus on the likely cellular mechanisms by which aging may increase cerebromicrovascular fragility and promote development of CMHs: increased presence of senescent cells in the cerebral microcirculation. The central hypothesis is that activation of p16-dependent cellular senescence program is responsible for a pro-fragility microvascular phenotype: senescent cells release activated matrix metalloproteinases ("senescence-associated secretory phenotype" or SASP) promoting degradation of collagen and remodeling of extracellular matrix thus creating loci of least resistance that can easily burst upon induction of hypertension. We will combine advanced cellular imaging techniques and cutting-edge transcriptomics to investigate microvascular structure and gene expression in senescent endothelial and smooth muscle cells in the cerebral microvessels of aged mice. Our prediction, based on our working hypothesis, is that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse model) or by pharmacological means will protect the structural integrity of cerebral vessels preventing the development of CMHs. Based on our extensive experience in the field of vascular aging research we are well positioned to test our hypotheses using innovative mouse models of CMHs. The proposed work is expected to identify fundamental mechanisms underlying genesis of CMHs in aging. These outcomes will have an important positive impact, since they will enable us to develop novel, translationally relevant interventional strategies for prevention of CMHs, protecting cerebral function in the elderly.
Funder: American Heart Association
Amount: $136,800
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2021-04-01
End date: 2023-03-31
Investigators: Adam Nyul Toth, Adam Nyul Toth
Institution: Board of Regents of the University of Oklahoma, Health Sciences Center
Funded outputs count: 2
Funder award ID: 834339
OpenAlex ID: G3208477429