Investigation into Heart Aging

心脏老化研究

基本信息

批准号：
9027562
负责人：
Zhongjie Sun
金额：
$ 46.82万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027562
关键词：
20 year old Address Affect Age Aging Aging-Related Process Animal Model Attenuated Blood Cardiac Cardiac Myocytes Cardiovascular Diseases Collagen Data Development Disease Down-Regulation Environment Failure Fibroblasts Fibrosis Gene Expression Genes Goals Health Hearing Heart Heart Diseases Heart failure High Prevalence Human Individual Investigation Kidney Knock-out Longevity Mediating Molecular Mus Mutation Pathogenesis Pathway interactions Population Positioning Attribute Prevalence Prevention strategy Preventive Preventive Intervention Proteins Research Risk Factors Role Structure Testing Therapeutic Therapeutic Intervention Up-Regulation Work adenylyl cyclase 6 age related aged aging gene anti aging coronary fibrosis effective intervention heart function in vivo innovation insight klotho protein mortality new therapeutic target novel novel strategies novel therapeutic intervention overexpression prevent scleraxis

项目摘要

DESCRIPTION (provided by applicant): The heart function declines in the aged population. At age 80 years, LV contractile function is less than half of what it was at age 20 years. Aging, even in apparently healthy individuals without overt cardiovascular disease, is associated with damaged heart structure and comprised cardiac reserve function. Aging is a recognized risk factor for heart diseases. For instance, the prevalence of heart disease increases with age. Indeed, the mortality from heart diseases is higher in the aged than in the young population. Klotho is a recently-discovered anti- aging gene. Mutation of klotho gene expedites the aging process and shortens the life-span while over- expression of klotho slows the aging process and extends the life-span in mice. Klotho is predominately expressed in kidneys and secreted into the blood. In humans, the level of circulating klotho declines in the aged population. The objective of this application is to investigate, in animal models, if klotho deficiency causes hear damage and assess if in vivo expression of klotho or supplement of klotho protein prevents or attenuates aging-associated heart damage. The central hypothesis is that klotho gene deficiency impairs cardiomyocyte contractile function and upregulates collagen synthesis thereby impairing heart function and causing heart remodeling (fibrosis), respectively. The rationale for the proposed research is that if klotho deficiency causes heart damage, then, in vivo upregulation of klotho gene expression or supplement of klotho protein may be a novel approach for therapeutic intervention to prevent or attenuate aging-related heart damage and failure. This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches. The two specific aims are: (1) Determine if klotho deficiency causes heart failure and remodeling and investigate the underlying molecular mechanisms. (2) Investigate if kidney-specific expression of klotho gene or supplement of klotho protein attenuates aging-associated heart damage. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address aging-associated heart damage which affects a large population but remains poorly explored. The results will reveal novel molecular pathways that mediate the pathogenesis of aging-related heart failure and remodeling. Completion of this project may provide new insights into therapeutic strategies for aging-related heart damage.

描述（申请人提供）： 80 岁时，心脏功能下降，左心室收缩功能不到 20 岁时的一半，即使是表面上健康且没有明显心血管疾病的人。与受损的心脏结构和心脏储备功能有关。例如，心脏病的患病率随着年龄的增长而增加。事实上，老年人的心脏病死亡率高于年轻人。。 Klotho是最近发现的抗衰老基因，klotho基因的突变会加速衰老过程并缩短寿命，而klotho基因的过度表达会减缓衰老过程并延长小鼠的寿命。在人类中，老年人群中循环的 klotho 水平下降。本应用的目的是在动物模型中研究 klotho 缺乏是否会导致听力损伤。 klotho 的体内表达或 klotho 蛋白的补充可预防或减轻与衰老相关的心脏损伤。核心假设是 klotho 基因缺陷会损害心肌细胞收缩功能并上调胶原合成，从而损害心脏功能并导致心脏重塑（纤维化）。拟议研究的理由是，如果 klotho 缺乏导致心脏损伤，那么，体内上调 klotho 基因表达或补充 klotho 蛋白可能是一种新的治疗干预方法，以预防心脏损伤或减轻与衰老相关的心脏损伤和衰竭。这一目标将通过结合几种新颖的方法追求两个连贯的具体目标来实现。这两个具体目标是：（1）确定 klotho 缺乏是否会导致心力衰竭和重塑，并研究其原因。 (2) 研究 klotho 基因的肾脏特异性表达或 klotho 蛋白的补充是否可以减轻与衰老相关的心脏损伤。这项工作具有创新性且意义重大，因为它利用了最先进的方法来解决这一问题。与衰老相关的心脏损伤影响着大量人群，但尚未得到充分探索。该研究结果将揭示介导与衰老相关的心力衰竭和重塑的发病机制的新分子途径，该项目的完成可能会为衰老相关的治疗策略提供新的见解。心脏损伤。