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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.

描述（由申请人提供）：血管平滑肌细胞（vSMC）在心血管疾病（CVD）的病理生理学中发挥关键作用。新的证据表明，血管壁内的干细胞分化为血管平滑肌细胞，并且是动脉壁重塑和修复的积极贡献者。这一信息强调了一个新的细胞靶点，用于研究已知影响 CVD 的药物，以及治疗血管疾病的新的潜在治疗靶点。虽然饮酒 (EtOH) 是影响 CVD 发病率和严重程度的一个公认因素，但其对常驻血管干细胞再生能力的影响尚未确定。与血管疾病进展有关的干细胞群包括位于内侧外膜边界的 Sca1+ 外膜祖细胞 (APC)。在血管损伤模型中，APC 增殖并分化为侵入内膜的 vSMC。有几种因子被描述为干细胞自我更新、分化和生长的调节因子，其中最著名的是形态发生素 sonic humig (Shh)。我们已经证明，与 APC 群体共定位的 a-肌动蛋白阴性、Hh 阳性细胞位于正常血管的内侧外膜边界，随后在损伤后出现在 a-肌动蛋白阳性内侧和内膜层内。 Hedgehog 信号传导由分泌的 Shh 配体与跨膜受体 Patched (Ptch) 的结合触发，随后由属于 Gli 家族的转录效应子介导。 Hedgehog 通路的成分在体内血管损伤后被诱导，并且 Hedgehog - Notch 信号轴在体外控制 vSMC 生长和表型。至关重要的是，我们最近发现，血管壁内原位刺猬信号的局部抑制可以减轻损伤后的内膜内侧增厚。我们的初步数据现在表明，酒精调节vSMC中hedgehog信号成分的表达，并且Shh在体外控制干细胞向vSMC的转变。因此，我们的总体假设是，酒精会干扰常驻血管干细胞的更新和/或分化，从而通过影响刺猬信号传导来影响血管重塑和心血管疾病。我们将在体外 (APC) 和体内（颈动脉结扎小鼠动脉粥样硬化模型）测试这一假设的有效性，并研究酒精调节 Hedgehog 信号传导的机制，重点关注 Ptch1 受体 -Caveolin-1 在脂筏中的共定位以及 E3 泛素连接酶的降解。破译酒精影响心血管疾病的机制具有重要的临床重要性和意义。

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.