Klotho and cardiovascular disease in the Honolulu Heart Program

檀香山心脏计划中的 Klotho 和心血管疾病

• 批准号: 8262248
• 负责人: RICHARD D SEMBA
• 金额: $ 12.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-25 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262248
• 关键词: Address; Adult; Aging; Animal Disease Models; Animal Model; Animals; Atherosclerosis; Atrophic condition of skin; Award; Binding; Blood Circulation; Bone Density; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cessation of life; Cohort Studies; Coronary Arteriosclerosis; Coronary heart disease; Country; Data; Disease; Elderly; Endothelium; Enzyme-Linked Immunosorbent Assay; Event; Functional disorder; Gene Delivery; Genes; Goals; Greek; Hawaii; Health; Heart; Hormones; Human; Hypertension; Impaired cognition; Individual; Inflammation; Integral Membrane Protein; Intervention; Investigation; Italy; Japanese American; Knowledge; Life; Longevity; Maintenance; Measures; Medical; Membrane; Minority; Morbidity - disease rate; Mus; Mutant Strains Mice; Mythology; Names; Nitric Oxide; Participant; Pathogenesis; Pathway interactions; Phenotype; Plasma; Population; Production; Prospective Studies; Public Health; Regulation; Renal Hypertension; Risk; Risk Factors; Role; Serum; Single Nucleotide Polymorphism; Stroke; Therapeutic; Therapeutic Intervention; Transgenic Mice; United States National Institutes of Health; Vascular Permeabilities; Visit; Wild Type Mouse; aging gene; anti aging; base; cardiovascular risk factor; cohort; follow-up; human disease; in vivo; indexing; innovation; insight; interest; men; middle age; mortality; new therapeutic target; novel; overexpression; population based; programs; receptor; sarcopenia

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 and that circulating klotho levels significantly increase the C-index beyond traditional cardiovascular risk factors in relation to prevalent cardiovascular disease. Based upon knowledge of klotho and our preliminary data, we hypothesize that men with low circulating klotho levels are at increased risk of cardiovascular events and mortality. We propose to characterize the relationship of serum klotho as a predictor of incident coronary heart disease, stroke, and cardiovascular and all-cause mortality in the Honolulu Heart Program, an NIH-supported, prospective study of coronary heart disease and stroke in Japanese-American men. This project will determine whether serum klotho is a major independent 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.

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