Anti-aging gene klotho: a novel therapeutic target in calcific aortic valve disease

描述（由申请人提供）：随着衰老、糖尿病、高血压等危险因素的日益普遍，再加上遗传因素，会扰乱主动脉瓣的细胞和分子机制，导致钙化性主动脉瓣病（CAVD），最终导致主动脉瓣狭窄。手术置换主动脉瓣仍然是治疗这种疾病的唯一和最后的选择。2009年，超过3万个主动脉瓣被替换。严重主动脉瓣狭窄患者未接受瓣膜置换术，在症状出现一年后的死亡率为37%。然而，更换瓣膜容易失效，需要额外的手术。由于该病的病因不明，目前尚无有效的药物治疗方法。因此，开发新的靶点和策略来开发治疗CAVD的概念突破是至关重要的。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。老年人群中循环klotho水平下降，而老年人群中CAVD患病率上升。本应用的目的是在动物模型中确定klotho缺乏症是否是CAVD的原因，以及klotho基因传递或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互补的具体目标来实现这一目标。(1)确定klotho缺乏症是否导致CAVD，并研究其分子机制。(2)探讨体内给药klotho基因或蛋白可减轻或逆转衰老加速小鼠的CAVD的假设。所提出的工作是创新和重要的，因为它采用了最先进的方法来解决影响大量老年人口但仍未充分探索的CAVD。结果将揭示衰老相关CAVD的新病因。该研究将为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.