Anti-aging Gene Klotho: A Novel Therapeutic Target for Calcific Aortic Valve Dise

抗衰老基因Klotho：钙化性主动脉瓣疾病的新治疗靶点

• 批准号: 8814275
• 负责人: Zhongjie Sun
• 金额: $ 36.45万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814275
• 关键词: Abbreviations; Address; Adult; Affect; Age; Aging; Aging-Related Process; Alkaline Phosphatase; Animal Model; Aortic Valve Stenosis; Attenuated; Cardiovascular Diseases; Cell Adhesion Molecules; Chronic Kidney Failure; Collagen; Complement; Coupled; Deposition; Development; Diabetes Mellitus; Disease; Endothelial Cells; Environment; Etiology; Failure; Gene Delivery; Genes; Genetic; Goals; Heart Diseases; High Prevalence; Human; Hypertension; Inbred Strain; Inflammation; Kidney; Knock-out; Longevity; Matrix Metalloproteinases; Medical; Molecular; Mus; Mutation; Operative Surgical Procedures; Oxidative Stress; Pathogenesis; Patients; Population; Prevalence; Prevention strategy; Proteins; Research; Resistance; Risk Factors; Role; Serum; Surgical Valves; Symptoms; Testing; Therapeutic; Work; aged; aging gene; anti aging; aortic valve; aortic valve disorder; aortic valve replacement; calcification; endothelial dysfunction; in vivo; innovation; insight; klotho protein; matrix Gla protein; mortality; new therapeutic target; novel; prevent; public health relevance; scleraxis; senescence; transcription factor; valve replacement

DESCRIPTION (provided by applicant): The mounting prevalence of risk factors such as aging, diabetes, and hypertension, coupled with genetic factors can perturb the cellular and molecular mechanism of the aortic valves leading to calcific aortic valve disease (CAVD) and ultimately aortic stenosis. Surgical replacement of the aortic valve remains the only and the last choice for the disease. Over 30,000 aortic valves were replaced in 2009. Patients with severe aortic stenosis who do not receive surgical valve replacement have a mortality rate of 37% at one year after symptom onset. However, replacement valves are susceptible to failure, necessitating additional surgeries. There currently is no effective medical therapy for CAVD due to the unknown etiology of the disease. Therefore, a conceptual breakthrough to develop novel targets and strategies to develop a cure for CAVD is paramount. Klotho is a recently-discovered anti- aging gene and is predominately expressed in kidneys. Klotho is a secreted protein. The level of circulating klotho declines in the aged population while the prevalence of CAVD increases in the aged population. The objective of this application is to determine, in animal models, if klotho deficiency is a causal factor of CAVD and if klotho gene delivery or klotho protein supplement could serve as an effective therapeutic strategy for CAVD. We will accomplish this objective by pursuing the following two complement specific aims. (1) Determine if klotho deficiency causes CAVD and investigate its molecular mechanism. (2) Investigate the hypothesis that in vivo klotho gene or protein delivery will attenuate or reverse CAVD in senescence-accelerated mice. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address CAVD which affects a large aged population but remains poorly explored. The results will reveal a novel etiological factor for senescence-related CAVD. The proposed research will provide important insights into therapeutic strategies for CAVD.

描述（由申请人提供）：风险因素（如衰老、糖尿病和高血压）的发病率不断增加，加上遗传因素，可干扰主动脉瓣的细胞和分子机制，导致钙化性主动脉瓣疾病（CAVD），最终导致主动脉瓣狭窄。主动脉瓣置换术仍是治疗该病的唯一和最后选择。2009年更换了30 000多个主动脉瓣。没有接受外科瓣膜置换术的严重主动脉瓣狭窄患者在症状发作后一年的死亡率为37%。然而，置换瓣膜容易失效，需要额外的手术。由于CAVD的病因不明，目前尚无有效的药物治疗方法。因此，开发新的靶点和策略以开发CAVD的治愈方法的概念突破至关重要。Klotho是最近发现的抗衰老基因，主要在肾脏中表达。Klotho是一种分泌蛋白。老年人群中循环klotho水平下降，而老年人群中CAVD的患病率增加。本申请的目的是在动物模型中确定klotho缺乏是否是CAVD的致病因素，以及klotho基因递送或klotho蛋白补充剂是否可以作为CAVD的有效治疗策略。我们将通过以下两个相辅相成的具体目标来实现这一目标。(1)确定klotho缺乏是否导致CAVD并研究其分子机制。(2)研究体内klotho基因或蛋白质递送将减弱或逆转加速衰老小鼠中的CAVD的假设。拟议的工作是创新的和重要的，因为它利用最先进的方法来解决CAVD影响了大量的老年人口，但仍然很少探索。这些结果将揭示衰老相关CAVD的新病因。拟议的研究将为CAVD的治疗策略提供重要的见解。