Human Microphysiological System to Study LINC Complex Mediated Force Imbalance in Progeria and Cardiovascular Diseases
Description: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare but fatal genetic disease that causes premature aging symptoms in young children. Complications from Cardiovascular disease (CVD) is the leading cause of death in these patients. HGPS is caused by a point mutation in the LMNA gene, which produces progerin. Progerin has also been detected in skin biopsy samples from healthy donors. Lamin A supports the nuclear mechanical properties to protect the genome inside. However, the accumulation of progerin, instead of lamin A, at the nuclear membrane alters the nuclear properties and shapes. The forces formed outside the nucleus are transmitted into the nucleus through the Linker of nucleoskeleton and cytoskeleton (LINC) complex. Disruption of such connection induces malfunctions in cells and tissues. Study has identified that abnormal expression of LINC complex protein causes force imbalance in HGPS fibroblasts cultured on 2D surface. Although 2D cell culture could elucidate some interesting insights, it is essential to test the findings in a more physiologically relevant system. Furthermore, how force imbalance affect the endothelial cells (EC) and smooth muscle cells (SMC), the two major cell types in blood vessel is poorly known. I hypothesize that this force imbalance will cause defects in ECs and SMCs, which later lead to the initiation of CVDs. The tissue-engineered blood vessel (TEBV) developed in our lab could closely recapitulate many features in CVDs. It is worth noted that it is the first TEBV system that shows endothelial-mediated vasodilation. With the ECs and SMCs derived from HGPS iPSC, in this proposal, I will first identify the specific role of each LINC complex protein in inducing force imbalance in ECs and SMCs by knockdown approach with highly specific molecular constructs and drug inhibitors (Aim1) and then use the TEBVs to study how this LINC complex-mediated force imbalance induces EC activation, loss of SMCs and production of pro-inflammatory cytokines in the blood vessel and promote the initiation of CVDs (Aim2). Upon the end of this project, I will identify the detailed mechanism of how LINC complex-mediated force imbalance in HGPS could contribute to the overall progression of the disease. Since there are similarities between HGPS derived and age-related CVDs, the findings in this study will add to our understanding of general CVDs.
Funder: American Heart Association
Amount: $145,000
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2022-01-01
End date: 2023-03-31
Investigators: Qiao Zhang, Qiao Zhang
Institution: Duke University
Funded outputs count: 1
Funder award ID: 905681
OpenAlex ID: G3509314568