Targeting a lipid-mediated pro-longevity pathway as Alzheimer's therapy

靶向脂质介导的长寿途径作为阿尔茨海默病的治疗方法

基本信息

批准号：
10197488
负责人：
Jin Wang
金额：
$ 4.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2018-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197488
关键词：
Address Affect Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid deposition Animal Model Attenuated Behavioral Biochemical Biological Models Biology of Aging Body Weight Brain Caenorhabditis elegans Cause of Death Cell Nucleus Chemicals Chronic Clinical Collaborations Complex Data Dementia Diabetes Mellitus Disease Disease Management Disease Progression Dose Elderly Electrophysiology (science)Environmental Risk Factor Etiology FDA approved Fatty acid glycerol esters Functional disorder Future Gene Expression Genetic Geroscience Goals Health High Fat Diet Human Hyperinsulinism Incidence Individual Intervention Knock-in Knock-in Mouse Late Onset Alzheimer Disease Lead Lipids Longevity Longevity Pathway Mammals Mediating Medical Metabolic Metabolic dysfunction Metabolic stress Metabolism Mitochondria Modeling Molecular Molecular Chaperones Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nutritional Obesity Paralysed Pathologic Pathology Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Prevention Process Property Regulation Resistance Risk Risk Factors Rodent Role Science Senile Plaques Signal Pathway System Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Tissues Toxic effect Transgenes Transgenic Mice Transgenic Organisms United States Weight Gain absorption age related aged analog base behavioral impairment chemical stability comorbidity design effective therapy feeding healthspan healthy aging human old age (65+)improved innovation insight lipid metabolism metabolic profile middle age mouse model multidisciplinary novel oleoylethanolamide overexpression oxidation prevent public health relevance tau Proteins therapeutic target therapy outcome

项目摘要

Abstract Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes 60% to 70% of cases of dementia and is the 6th leading cause of death in the United States. AD usually manifests in individuals over 65 years old and the incidence increases with age. Currently, there are five FDA-approved Alzheimer's drugs that only provide temporary symptomatic relief but do not prevent or delay the disease progression. Thus, developing effective therapies of AD represent an urgent medical need. Although the etiology of AD remains elusive, aging is the greatest known risk factor. As such, strategies that improve healthy aging may serve as effective means for AD management. In this proposal, we will interrogate this idea by focusing on a naturally occurring lipid molecule, oleoylethanolamide (OEA), that we recently identified to improve lifespan and healthspan in Caenorahbditis elegans. Importantly, OEA and its signaling pathways are highly conserved from worm to mammals, including humans, and OEA has been shown to regulate feeding and body weight and inhibit high-fat diet induced obesity and metabolic dysfunctions in rodents. Our proposal is supported by strong scientific premise because alterations in lipid metabolism and storage become prevalent during aging, while midlife obesity and its metabolic comorbidities such as hyperinsulinemia, diabetes, and altered lipid metabolism increase the risk of late-onset AD. Thus, lipid regulators that promote metabolic health and longevity like OEA may be a promising target for the prevention and treatment of AD. This multi-PI application joins force of three individuals with outstanding expertise in aging biology and lipid metabolism (Meng Wang), AD mouse models (Hui Zheng), and medicinal chemistry (Jin Wang), and is built on our ongoing collaborations. Together we will 1) elucidate the effects of OEA in AD C. elegans models and develop and test new and highly potent OEA analogs; 2) determine the therapeutic effect of OEA analogs in AD mouse models; and 3) understand the role of OEA analogs in AD under high metabolic stress conditions. Our proposal is highly innovative as it addresses a new concept to apply pro- longevity compounds for AD therapy through a novel lipid-mediated mechanism. It is also highly significant as it is directly therapeutically relevant and tackles a disease of unmet medical needs.

摘要阿尔茨海默病 (AD) 是一种慢性神经退行性疾病，导致 60% 至 70% 的痴呆病例，是美国第六大死因。 AD通常出现在65岁以上的个体中，并且发病率随着年龄的增长而增加。目前，有五种 FDA 批准的阿尔茨海默病药物只能暂时缓解症状，但不能预防或延缓疾病进展。因此，开发有效的 AD 疗法代表了迫切的医疗需求。尽管 AD 的病因仍然难以捉摸，但衰老是已知的最大风险因素。因此，改善健康老龄化的策略可能成为 AD 管理的有效手段。在本提案中，我们将通过关注天然存在的脂质分子油酰乙醇酰胺（OEA）来质疑这一想法，我们最近发现它可以改善秀丽隐杆线虫的寿命和健康状况。重要的是，OEA 及其信号通路从蠕虫到包括人类在内的哺乳动物都高度保守，并且 OEA 已被证明可以调节啮齿动物的摄食和体重，并抑制高脂肪饮食引起的肥胖和代谢功能障碍。我们的建议得到了强有力的科学前提的支持，因为脂质代谢和储存的改变在衰老过程中变得普遍，而中年肥胖及其代谢合并症（如高胰岛素血症、糖尿病和脂质代谢改变）会增加迟发性 AD 的风险。因此，像 OEA 这样促进代谢健康和长寿的脂质调节剂可能是预防和治疗 AD 的有希望的目标。这项多 PI 应用由三位在衰老生物学和脂质代谢 (Meng Wang)、AD 小鼠模型 (Hui Cheng) 和药物化学 (Jin Wang) 方面拥有杰出专业知识的个人联合起来，并建立在我们持续合作的基础上。我们将共同 1) 阐明 OEA 在 ADC 线虫模型中的作用，并开发和测试新的高效 OEA 类似物； 2)确定OEA类似物在AD小鼠模型中的治疗效果； 3) 了解 OEA 类似物在高代谢应激条件下在 AD 中的作用。我们的提案具有高度创新性，因为它提出了一个新概念，即通过一种新型脂质介导机制将长寿化合物应用于 AD 治疗。它也非常重要，因为它与治疗直接相关并解决医疗需求未得到满足的疾病。