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Klotho and the pathogenesis of cardiovascular disease

Klotho 与心血管疾病的发病机制

基本信息

批准号：
8371479
负责人：
RICHARD D SEMBA
金额：
$ 42万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8371479
关键词：
Address Adult Age Aging Animal Disease Models Animal Model Animals Atherosclerosis Atrophic condition of skin Award Binding Blood Circulation Bone Density California Cardiac Cardiovascular Diseases Cardiovascular system Cell Adhesion Molecules Cessation of life Cohort Studies Communities Congestive Heart Failure Coronary Arteriosclerosis Coronary heart disease Country Data Disease Elderly Endothelium Enzyme-Linked Immunosorbent Assay Event Functional disorder Gene Delivery Genes Goals Greek Health Hormones Human Hypertension Impaired cognition Individual Inflammation Integral Membrane Protein Intervention Investigation Italy Knowledge Life Longevity Longitudinal Studies Maintenance Maryland Measures Medial Mediating Medical Membrane Morbidity - disease rate Mus Mutant Strains Mice Myocardial Infarction Mythology Names Nitric Oxide North Carolina Participant Pathogenesis Pathway interactions Pennsylvania Peripheral arterial disease Phenotype Plasma Population Production Public Health Regulation Renal Hypertension Risk Risk Factors Role Serum Single Nucleotide Polymorphism Stroke Study of serum Therapeutic Therapeutic Intervention Thick Transgenic Mice Transient Ischemic Attack United States National Institutes of Health Vascular Permeabilities Visit Wild Type Mouse aging gene anti aging base cardiovascular risk factor follow-up genome wide association study human disease in vivo innovation insight interest intima media mortality new therapeutic target novel overexpression population based receptor sarcopenia

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in western countries. Despite substantial medical progress in identifying modifiable cardiovascular risk factors, a significant proportion of individuals with cardiovascular disease have no known risk factors. Klotho is a recently discovered hormone found to protect against endothelial dysfunction, atherosclerosis, and cardiovascular disease in mice, as well as to extend lifespan. The klotho gene encodes a single-pass transmembrane protein that exists as a circulating hormone and as a membrane-bound co-receptor. Klotho regulates nitric oxide production, vascular permeability, suppression of inflammation, and expression of adhesion molecules by the endothelium. In the absence of klotho hormone, endothelial dysfunction and hypertension occur in animal models, which are reversible or preventable with in vivo delivery of the klotho gene. Until recently, there was no way to measure levels of klotho in the circulation. We are the first to measure klotho levels in a large number of people. Our preliminary data support the premise that klotho is protective against cardiovascular disease in humans. Based upon knowledge of klotho and our preliminary data, we hypothesize that older people with low circulating klotho levels are at increased risk of cardiovascular events and mortality, and that klotho levels are associated with impaired brachial flow-mediated dilation. We propose to characterize the relationship of serum klotho with prevalent cardiovascular disease (myocardial infarction, angina, stroke, congestive heart failure, peripheral artery disease, transient ischemic attack), carotid intima-media thickness, brachial flow-mediated dilation, cardiovascular events and mortality in the Cardiovascular Health Study, an NIH-supported, population-based, longitudinal study of coronary heart disease and stroke in US adults. We will also conduct a genome-wide association study of serum klotho levels. This project will determine whether serum klotho is a major risk factor for cardiovascular disease and will provide novel insight into the role of klotho in human health. The project should provide the rationale and evidence for klotho as a potential novel therapeutic target for intervention in cardiovascular disease. PUBLIC HEALTH RELEVANCE: This project is relevant to public health as it aims to characterize the relationship between klotho, a recently discovered hormone, with cardiovascular disease and cardiovascular mortality in older US adults.

描述（由申请人提供）：心血管疾病是西方国家发病率和死亡率的主要原因。尽管在确定可改变的心血管危险因素方面取得了实质性的医学进展，但很大一部分患有心血管疾病的人