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率的主要原因。尽管在识别可修改的心血管危险因素方面有很大的医学进展，但心血管的患者很大一部分疾病没有已知的危险因素。克洛索（Klotho）是一种最近发现的激素，可防止小鼠的内皮功能障碍，动脉粥样硬化和心血管疾病，以及延长寿命。 Klotho基因编码作为循环激素和膜结合的共受体的单通跨膜蛋白。 Klotho调节一氧化氮的产生，血管通透性，炎症的抑制以及内皮的粘附分子的表达。在没有克洛托激素的情况下，在动物模型中发生内皮功能障碍和高血压，由于klotho基因的体内递送是可逆或可预防的。直到最近，还没有办法测量循环中克洛索的水平。我们是第一个在许多人中衡量Klotho级别的人。我们的初步数据支持克洛托（Klotho）对人类心血管疾病的保护。基于对Klotho的了解和我们的初步数据，我们假设循环较低的Klotho水平的老年人患心血管事件和死亡率的风险增加，并且Klotho水平与臂流动介导的扩张受损有关。我们建议表征血清Klotho与患心血管疾病（心肌梗塞，心绞痛，中风，充血性心力衰竭，周围动脉疾病，瞬时缺血的关系）的关系攻击），在心血管健康研究中，颈动脉内膜厚度，臂流动介导的扩张，心血管事件和死亡率，这是美国成年人的NIH支持的，基于NIH的基于人群的冠状动脉疾病和中风的纵向研究。我们还将对血清Klotho水平进行全基因组的关联研究。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。该项目应为克洛索（Klotho）提供理由和证据，作为干预心血管疾病的潜在新型治疗靶标。