权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Integrative Mechanisms of Vascular Aging

血管老化的综合机制

基本信息

批准号：
10608880
负责人：
Anthony John Donato
金额：
$ 47.28万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608880
关键词：
Age Aging Aorta Arteries Attenuated Binding Biological Availability Blocking Antibodies Blood Vessels C57BL/6 Mouse CD44 Antigens CD44 gene Cardiovascular Diseases Cardiovascular system Cause of Death Cell Communication Cell physiology Characteristics Clustered Regularly Interspaced Short Palindromic Repeats Complex Consensus Custom Data Deterioration Development Diet Dietary Supplementation Elasticity Elderly Endothelial Cells Endothelium Enzymes Event Female Functional disorder Gel Gene Expression Genetic Glycocalyx Glycosaminoglycans Human Hyaluronan Immune Impairment Inflammation Knock-out Ligands Longevity Maintenance Measures Mediating Modeling Molecular Weight Mus Nitric Oxide Outcome Outcome Assessment Outcome Measure Permeability Phenotype Play Production Property Protein Isoforms Reporting Role Signal Transduction Structure Supplementation Surface Tamoxifen Therapeutic Uses Thick Tissues Vascular Diseases Vascular Endothelium Vasodilation Vasodilator Agents age effect age related anti aging arterial stiffness efficacy evaluation endothelial dysfunction gain of function hyaluronan synthase 1 improved knock-down loss of function male middle age mouse model novel novel therapeutics overexpression receptor

项目摘要

Arterial aging is characterized by diminished endothelium dependent dilation (EDD) and large artery stiffening. The endothelium is a critical modulator of arterial function participating in the control of vascular tone, nitric oxide production and bioavailability, large artery stiffening, inflammation, and barrier function. Deterioration of the glycocalyx, a gel-like structure bound to the luminal surface of the endothelium, is accompanied by age- associated vascular dysfunction by altering these functions of the vascular endothelium. Although the glycocalyx is primarily known for its role in the microvasculature, it also impacts central cardiovascular features, and deterioration or phenotypic changes in the glycocalyx with advancing age that likely impair larger arterial function. The thickness of the glycocalyx decreases in the microvasculature of both mice and humans with advancing age and this appears to be accompanied by alterations in its constituent molecules. Although there is no consensus on whether the content of hyaluronan (HA), one of the primary glycosaminoglycan components of the endothelial glycocalyx, decreases across the lifespan, there is evidence of a phenotypic shift from high (HMW-HA) to low molecular weight. The importance of maintaining a youthful, HMW-HA, profile is demonstrated by observations that HMW-HA has anti-aging, vasoprotective properties. Among the three HA synthase (HAS) enzymes, HAS2 produces the majority of HMW-HA. However, although reductions in HAS2 gene expression have been reported in non-vascular tissues with aging, arterial data concerning the effects of aging on HAS2 expression are limited. Thus, despite evidence suggesting that alterations in the glycocalyx; its constituent, HA; and the enzyme responsible for its production, HAS2, are coincident with age-related arterial dysfunction, their causal role remains elusive. Here, we will utilize endothelial specific, loss and gain of function mouse models to elucidate the role of HAS2 and HA phenotype in alterations in the glycocalyx, arterial function, inflammation, and permeability across the lifespan of mice. We will also interrogate the role of a HA receptor, CD44, in these effects. Last, we will assess the efficacy of dietary supplementation with HMW-HA to improve these aspects of arterial function in advancing age and explore underlying mechanisms. The results will elucidate novel mechanisms of age-related vascular dysfunction as well as demonstrate proof-of-concept for a new therapeutic to ameliorate age-associated arterial dysfunction that is easily translatable to humans.