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

描述(由申请人提供)：年龄、糖尿病和高血压等危险因素的日益流行，加上遗传因素，可以扰乱主动脉瓣的细胞和分子机制，导致钙化性主动脉瓣疾病(CAVD)，最终导致主动脉狭窄。外科手术替换主动脉瓣仍然是治疗这种疾病的唯一也是最后的选择。2009年，超过30,000例主动脉瓣被替换。没有接受外科瓣膜置换术的重度主动脉瓣狭窄患者在症状出现一年后的死亡率为37%。然而，替换瓣膜很容易失效，需要进行额外的手术。由于病因不明，目前尚无有效的药物治疗CAVD。因此，在概念上取得突破，开发新的靶点和策略，以开发治疗CAVD的方法是至关重要的。Klotho是最近发现的一种抗衰老基因，主要在肾脏中表达。Klotho是一种分泌蛋白质。老年人群循环血钾水平下降，CAVD患病率上升。这项应用的目的是在动物模型中确定Klotho缺乏是否是CAVD的原因，以及Klotho基因转移或Klotho蛋白补充是否可以作为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，并探讨其分子机制。(2)探讨Klotho基因或蛋白体内注射可减弱或逆转加速衰老小鼠CAVD的假说。这项拟议的工作具有创新性和重大意义，因为它利用最先进的方法来解决影响大量老年人口但仍未得到充分探索的CAVD。这一结果将揭示与衰老相关的CAVD的新的病因。这项拟议的研究将为CAVD的治疗策略提供重要的见解。

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.