Delay of Alzheimer's phenotypes by interventions that increase lifespan

拟议项目的目的是评估遗传和药理学操作是否 在阿尔茨海默病模型中， (AD)，最终目标是为这种毁灭性和昂贵的疾病开发更好的治疗方法 疾病目前还没有有效的治疗方法来治疗这种疾病，这种疾病正在走向破产 在不到30年的时间里，美国的医疗系统，尽管付出了巨大而昂贵的努力， 制药公司。拟议的研究采取了不同于 制药公司，这一直是基于特定的目标。相反，拟议的研究， 响应NIH PAR-18-596，基于这样的概念：由于年龄是AD的主要危险因素， 在人类中产生AD的基因在模型生物中产生病理， 尽管人类的寿命与年龄有很大关系，但增加寿命的操作也可能延迟人类AD的发作。 事实上，我们和其他人已经证明，一些基因操纵和药物， 增加模型器官C的寿命。在标准的转基因模型中， 这些发现中的一些导致了目前在人类AD中的临床试验。但只有 只有一小部分已知的可以延长寿命的操作方法已经过效果评估 关于AD模型的损伤。因此，我们建议通过评估 可靠地延长寿命的遗传和药理学操作对三种不同的 C. AD的elegans模型：肌肉特异性人Abeta 1-42（标准模型）和神经元特异性 人Abeta和Tau，两者都涉及人AD。我们也将反过来评估，如果药物， 已经发现在肌肉特异性保护的Abeta模型也会保护神经元- 特定的AD模型并延长寿命。基于成功的少数类似 我们和其他人已经进行的研究，导致人类AD的临床试验，我们预计， 目前提出的研究将大大增加可用的药物和药物靶点， 治疗人类AD。

The purpose of the proposed project is to assess if genetic and pharmacological manipulations that increase lifespan will similarly delay the onset of pathologies in models of Alzheimer's Disease (AD), with the ultimate goal of developing better treatments for this devastating and expensive disease. There are currently no effective treatments for this disease, which is on course to bankrupt the American health system in less than 30 years, despite tremendous and expensive efforts by pharmaceutical companies. The proposed studies take a different approach than taken by pharmaceutical companies, which have been based on specific targets. Instead the proposed studies, in response to NIH PAR-18-596, is based on the concept that since age is the major risk factor for AD, and genes that produce AD in humans produce pathologies in model organisms whose time-course scales with lifespan, manipulations that increase lifespan might also delay the onset of AD in humans. Indeed we and others have already demonstrated that some genetic manipulations and drugs that increase lifespan in the model organ C. elegans also delay symptoms in a standard transgenic model of AD, and some of these discoveries have led to current clinical trials in human AD. However, only a very small fraction of manipulations known to increase lifespan have been assessed for their effects on impairments in models of AD. We therefore propose to address this deficiency by assessing effects of genetic and pharmacological manipulations that reliably increase lifespan on three different C. elegans models of AD: muscle-specific human Abeta 1-42 (standard model), and neuronal-specific human Abeta and Tau, both implicated in human AD. We will also conversely assess if drugs we have already discovered to protect in the muscle-specific Abeta model will also protect in the neuron- specific models of AD and to increase lifespan. Based on the success of the small number of similar studies which we and others have carried out, leading to clinical trials in human AD, we anticipate that the presently proposed studies will vastly increase the available drugs and drug targets promising to treat human AD.