Vascular autophagy as a mediator of vascular aging and homeostasis

血管自噬作为血管衰老和稳态的介质

基本信息

批准号：
10186792
负责人：
TOREN FINKEL
金额：
$ 53.7万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186792
关键词：
Address Affect Aging Animals Arteries Autophagocytosis Blood Vessels Cardiovascular Diseases Cells Clustered Regularly Interspaced Short Palindromic Repeats Dementia Disease Disease model Elastin Fiber Endothelium Genes Genetic Genetic Diseases Homeostasis Human Impairment Individual Lamin Type A Longevity Malignant Neoplasms Mediator of activation protein Molecular Mus Mutation Myocardial Infarction Nature Nuclear Nuclear Envelope Nuclear Matrix Nucleotides Pathogenesis Pathologic Pathology Pathway interactions Patients Pharmacology Phenocopy Phenotype Production Progeria Proteins Role Secondary to Sirolimus Smooth Muscle Myocytes Specificity Stroke Syndrome Teenagers Testing Time Tissues Vascular Smooth Muscle age related base cell type de novo mutation experimental study human disease human subject induced pluripotent stem cell insight mTOR Inhibitor mortality mouse model mutant novel novel therapeutics prelamin A response small molecule

项目摘要

The role of autophagy in vascular homeostasis and vascular reactivity is poorly understood. In this proposal, we characterize mice lacking autophagic flux in the endothelial or smooth muscle cell layer. Remarkably, inhibiting autophagic flux in vascular smooth muscle cells appears to recapitulate aspects of the rare human disease Hutchinson-Gilford Progeria Syndrome (HGPS). This segmental progeriod condition is caused by a dominant mutation in the lamin A/C gene. While HGPS is an accelerated aging syndrome, most of the fatalities result from vascular complications (e.g. myocardial infarction and stroke). Analysis of human subjects, as well as characterization of mouse models of the disease, demonstrate profound changes in the large arteries. These changes are believed to be secondary to the vascular accumulation of progerin, an altered form of lamin A whose production is favored in patients with HGPS. Interestingly, progerin can also accumulate in the blood vessels of normal individuals as a function of aging. As such, these observations suggest that the lessons learned from this rare progeriod syndrome, HGPS, may have wider applications. In this proposal, we explore the role of autophagy in the segmental vascular pathology of HGPS. Using a variety of novel mouse models where autophagy has been conditionally deleted in the vessel wall, as well as human induced pluripotent stem cells (iPSCs) in which specific genes have been deleted via CRISPR- based strategies, we propose to study the mechanistic connection between impaired autophagy, HGPS pathology and normal vascular aging. As such, these studies provide the first characterization as to how endothelial and vascular smooth muscle cell autophagy regulates vascular homeostasis.

自噬在血管稳态和血管反应性中的作用尚不清楚。在在这个提议中，我们描述了内皮或平滑肌中缺乏自噬通量的小鼠细胞层。值得注意的是，抑制血管平滑肌细胞的自噬通量似乎概括了罕见的人类疾病哈钦森-吉尔福德早衰综合症（HGPS）的各个方面。这种节段性早衰病症是由核纤层蛋白 A/C 基因的显性突变引起的。虽然 HGPS 是一种加速衰老综合症，但大多数死亡都是由血管性死亡造成的并发症（例如心肌梗塞和中风）。对人类受试者的分析，以及该疾病的小鼠模型的表征，证明了大范围的深刻变化动脉。这些变化被认为是继发于早老素血管积累的，核纤层蛋白 A 的一种改变形式，其产生有利于 HGPS 患者。有趣的是，随着年龄的增长，早老素也会在正常个体的血管中积聚。因此，这些观察结果表明，从这种罕见的早衰中吸取的教训综合症，HGPS，可能有更广泛的应用。在本提案中，我们探讨了以下角色： HGPS 节段血管病理学中的自噬。使用各种新颖的鼠标血管壁中的自噬已被有条件删除的模型以及人类诱导多能干细胞（iPSC），其中特定基因已通过 CRISPR 删除基于策略，我们建议研究受损之间的机制联系自噬、HGPS 病理学和正常血管老化。因此，这些研究首次提供了内皮和血管平滑肌细胞自噬如何调节的表征血管稳态。