Role of histone deacetylase in premature endothelial senescent cells
Description: The overarching goal of this application is to test the hypothesis that Sirtuin-6 (SIRT6), a nuclear histone deacetylase, protects against accelerated ageing-induced endothelial cell senescence. SIRT6 associates with telomeric chromatin, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence . To date, endogenous SIRT6 expression levels have not been assessed in Hutchinson-Gilford Progeria Syndrome (HGPS) endothelial cells. Based on experimental data generated from the aforementioned experiments, it was hypothesized that (1) HGPS ECs will express lower levels of SIRT6 protein than normal ECs, which contribute to DNA damage and premature senescence, and (2) Overexpressing SIRT6 will prevent premature senescence in HGPS ECs. HGPS is a disorder of accelerated aging that is associated with myocardial infarction and stroke in the second decade of life due to severe atherosclerosis. The prelamin A mutation results in a truncated form of the progerin protein that becomes permanently farnesylated and which accumulates in the nuclear envelope. The accelerated atherosclerosis that occurs in these children is likely due to senescence of the endothelial and vascular smooth muscle cells. Senescent endothelial cells are 'atheroprone' in that they express adhesion molecules and chemokines that facilitate atherosclerosis, and generate increased amounts of reactive oxygen species that cause widespread aberrations in endothelial function. In this AHA Innovative Project Award, I propose to generate human induced pluripotent stem cell-derived endothelial cells (ECs) derived from induced pluripotent stem cells (iPSCs) from normal subjects and those with HGPS and perform comprehensive multidisciplinary analyses to characterize the functional and molecular phenotypes of vascular cells from HGPS patients before and after SIRT6 over expression. Although the vascular disease associated with HGPS also affects vascular smooth muscle cells, I will focus on the endothelial contribution to the accelerated atherosclerosis in HGPS. The overwhelming evidence that endothelial dysfunctions play a major role in the initiation and progression of atherosclerosis justifies this approach
Funder: American Heart Association
Amount: $200,000
Funding type: research
Funder scheme: Innovative Project Award
Start date: 2018-07-01
End date: 2020-09-30
Investigators: Rajarajan Thandavarayan, Rajarajan Thandavarayan
Institution: The Methodist Hospital Research Institute
Funded outputs count: 3
Funder award ID: 18IPA34170497
OpenAlex ID: G337131433