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

基本信息

批准号：
8473274
负责人：
RICHARD D SEMBA
金额：
$ 11.57万
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：
2012-05-25 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473274
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

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 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和死亡的主要原因。尽管在识别可改变的心血管危险因素方面取得了巨大的医学进展，但仍有相当一部分患有心血管疾病的人疾病没有已知的危险因素。 Klotho 是一种最近发现的激素，可以预防小鼠的内皮功能障碍、动脉粥样硬化和心血管疾病，并延长寿命。 klotho 基因编码单次跨膜蛋白，该蛋白作为循环激素和膜结合辅助受体存在。 Klotho 调节一氧化氮的产生、血管通透性、炎症抑制以及内皮细胞粘附分子的表达。在缺乏 klotho 激素的情况下，动物模型中会出现内皮功能障碍和高血压，而通过体内传递 klotho 基因，这些现象是可逆的或可预防的。直到最近，还没有办法测量循环中克洛索的水平。我们是第一个测量大量人群的 klotho 水平的人。我们的初步数据支持这样的前提：klotho 可以预防人类心血管疾病，并且循环 klotho 水平显着增加 C 指数，超出传统的心血管风险与流行的心血管疾病有关的因素。根据对 Klotho 的了解和我们的初步数据，我们假设循环 Klotho 水平较低的男性发生心血管事件和死亡的风险增加。我们建议在檀香山心脏计划中描述血清 klotho 作为冠心病、中风以及心血管和全因死亡率预测因子的关系，这是一项由 NIH 支持的日裔美国人冠心病和中风前瞻性研究男人。该项目将确定血清 klotho 是否是心血管疾病的主要独立危险因素，并将为 klotho 在人类健康中的作用提供新的见解。该项目应该为 klotho 作为心血管疾病干预的潜在新治疗靶点提供理论依据和证据。