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：
8499415
负责人：
RICHARD D SEMBA
金额：
$ 34.65万
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/8499415
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.

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。根据对 klotho 的了解和我们的初步数据，我们假设循环 klotho 水平较低的老年人发生心血管事件和死亡的风险增加，并且 klotho 水平与肱动脉血流介导的扩张受损有关。我们建议表征血清 klotho 与流行的心血管疾病（心肌梗死、心绞痛、中风、充血性心力衰竭、外周动脉疾病、短暂性脑缺血）的关系。心血管健康研究是一项由 NIH 支持、以人群为基础、针对美国成年人冠心病和中风的纵向研究，其中包括颈动脉内膜中层厚度、肱动脉血流介导的扩张、心血管事件和死亡率。我们还将开展血清 klotho 水平的全基因组关联研究。该项目将确定血清 klotho 是否是心血管疾病的主要危险因素，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。