Delay of Alzheimer's phenotypes by interventions that increase lifespan

通过延长寿命的干预措施延迟阿尔茨海默病表型

基本信息

批准号：
10161742
负责人：
CHARLES V MOBBS
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161742
关键词：
Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk American Amyloid beta-Protein Animal Model Bioinformatics CREBBP gene Caenorhabditis elegans Clinic Clinical Trials Disease Drug Industry Drug Targeting FRAP1 gene Failure Gene Expression Genes Genetic Goals Health system Histone Deacetylase Histone Deacetylase Inhibitor Human Impairment Intervention Investments Legal patent Link Literature Longevity Mammals Modeling Mus Muscle Mutation Myopathy Neurons Organ Model Pathology Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phenotype Phenylbutyrates Protective Agents Public Health Publishing RNA RNA Interference RNA interference screen Research Signal Pathway Sirolimus Standard Model Symptoms System Testing Thioctic Acid Time United States National Institutes of Health Urea cycle disorders Yeasts age related base design dietary restriction effective therapy genetic manipulation genome wide association study healthspan high-throughput drug screening histone acetyltransferase insight insulin-like signaling interest mouse model neurotoxic novel therapeutics protective effect response success tau Proteins therapy development transgenic model of alzheimer disease whole genome

项目摘要

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.

拟议项目的目的是评估遗传和药理操作是否这种增加的寿命同样会延迟阿尔茨海默氏病模型中的病理发作（AD），最终目标是为这种毁灭性和昂贵疾病。目前尚无对这种疾病的有效治疗尽管不到30年，美国卫生系统，尽管制药公司。拟议的研究采用的方法与制药公司，基于特定目标。相反，提出的研究，根据NIH Par-18-596的回应，是基于这样的概念，即自年龄是AD的主要风险因素，在人类中产生AD的基因在模型生物中产生病理使用寿命的尺度，增加寿命的操作也可能会延迟人类的AD发作。确实，我们和其他人已经证明了一些遗传操作和药物在模型器官中增加寿命C.秀丽隐杆线虫在标准转基因模型中还会延迟症状 AD的某些发现导致了当前的人类AD临床试验。但是，只有一个已经评估了已知增加寿命的操纵的很小一部分的影响关于AD模型的损害。因此，我们建议通过评估来解决这种缺陷遗传和药理操作的影响，可靠地增加三种不同的寿命秀丽隐杆线虫模型：肌肉特异性人Abeta 1-42（标准模型）和神经元特异性人类Abeta和Tau都涉及人类广告。我们还将相反评估我们是否使用毒品已经发现要在肌肉特异性ABETA模型中保护可以保护神经元的肌肉特异性ABETA模型广告的特定模型并增加寿命。基于少量类似的成功我们和其他人进行的研究，导致人类广告中的临床试验，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标的处理人类广告。