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Alcohol Regulation of Resident Vascular Stem Cells.

驻留血管干细胞的酒精调节。

基本信息

批准号：
9107329
负责人：
EILEEN M. REDMOND
金额：
$ 18.23万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-10 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107329
关键词：
Acetaldehyde Actins Adult Affect Alcohol consumption Alcohols Arteries Atherosclerosis Attenuated Binding Blood Vessels Cardiovascular Diseases Cause of Death Cell Differentiation process Cells Clinical Consumption Data Development Differentiation and Growth Disease Disease Progression Epidemiology Erinaceidae Ethanol Event Family Functional disorder Health In Situ In Vitro Incidence Injury Intellectual Property Invaded Investigation Laboratories Ligands Ligation Medial Mediating Membrane Microdomains Mesenchymal Modeling Molecular Mus Myocardial Infarction Myosin Heavy Chains Normal tissue morphology Pathology Pathway interactions Peripheral arterial disease Phenotype Play Population Proliferating Regulation Role SHH gene Severities Signal Transduction Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Stem cells Stroke Structural Genes Testing Time Vascular Diseases Vascular Smooth Muscle Vascular remodeling alcohol effect alpha Actin caveolin 1 cell growth cell type clinically relevant design hedgehog signal transduction in vivo interest intimal medial thickening migration morphogens mouse model neointima formation notch protein novel novel therapeutics receptor regenerative repaired research study self-renewal smoothened signaling pathway stem cell division stem cell population therapeutic target ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Vascular smooth muscle cells (vSMC) play a key role in the pathophysiology of cardiovascular disease (CVD). Emerging evidence suggests that stem cells present within the vessel wall differentiate to vSMC and are the active contributors to the remodeling and repair of the artery wall. This information highlights a new cell target to investigate for agents known to affect CVD, as well as a novel potential therapeutic target for treatment of vascular disease. While alcohol (EtOH) consumption is a well-established factor affecting the incidence and severity of CVD, its effects on the regenerative capacity of resident vascular stem cells have yet to be ascertained. A stem cell population implicated in vascular disease progression includes Sca1+ adventitial progenitor cells (APC) that reside at the medial adventitial boundary. APC proliferate and differentiate into vSMC that invade the intima in vascular injury models. Several factors have been described as regulators of stem cell self-renewal, differentiation and growth, most notably the morphogen sonic hedgehog (Shh). We have shown that a-actin negative, Hh-positive cells that co- localize with the APC population are located at the medial-adventitial boundary of normal vessels and later appear within the a-actin positive medial and intimal layer following injury. Hedgehog signaling is triggered by binding of the secreted Shh ligand with the transmembrane receptor Patched (Ptch) and is subsequently mediated by transcriptional effectors belonging to the Gli family. Components of the Hedgehog pathway are induced after vascular injury in vivo and a Hedgehog - Notch signaling axis controls vSMC growth and phenotype in vitro. Crucially, we have recently shown that local inhibition of hedgehog signaling in situ within the vessel wall attenuates intimal-medial thickening following injury. Our preliminary data now indicate that alcohol regulates the expression of hedgehog signaling components in vSMC, and that Shh controls stem cell transition to vSMC in vitro. Therefore, our overall hypothesis is that alcohol interferes with the renewal and/or differentiatio of resident vascular stem cells, and thus affects vessel remodeling and CVD, by affecting hedgehog signaling. We will test the validity of this hypothesis in vitro (APC) and in vivo (caroti ligation mouse model of atherosclerosis) and investigate the mechanism(s) whereby alcohol may modulate Hedgehog signaling, focusing on Ptch1 receptor-Caveolin-1 co-localization in lipid rafts and degradation by E3 ubiquitin ligases. Deciphering the mechanisms whereby alcohol affects cardiovascular disease is of major clinical importance and significance.

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Disease-Relevant Single Cell Photonic Signatures Identify S100β Stem Cells and their Myogenic Progeny in Vascular Lesions.

DOI：
10.1007/s12015-021-10125-x
发表时间：
2021-10
期刊：
Stem cell reviews and reports
影响因子：
4.8
作者：
Molony C;King D;Di Luca M;Kitching M;Olayinka A;Hakimjavadi R;Julius LAN;Fitzpatrick E;Gusti Y;Burtenshaw D;Healy K;Finlay EK;Kernan D;Llobera A;Liu W;Morrow D;Redmond EM;Ducrée J;Cahill PA
通讯作者：
Cahill PA

Caveolin-1 inhibition mediates the opposing effects of alcohol on γ-secretase activity in arterial endothelial and smooth muscle cells.