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Novel PPAR-gamma agonist selectively activate the ligand binding domain of PPAR-gamma and improve pathology and memory deficits in a 3xTg-Ad mouse model.

新型 PPAR-gamma 激动剂选择性激活 PPAR-gamma 的配体结合域，改善 3xTg-Ad 小鼠模型的病理和记忆缺陷。

基本信息

批准号：
8890576
负责人：
Rajesh H Amin
金额：
$ 36.2万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the leading causes of death in United States, suggesting the lack of therapies to prevent the progression of the disease. Continuous increase in the mortality rate due to AD indicates the urgent need for new drug discovery and further establishing the need for novel molecular targets for therapeutic potential. Many reports verify direct pathological links between AD and diabetes, which highlights the contribution of diabetes to the development of AD. Thiazolidinediones (TZDs) are insulin sensitizing peroxisomal proliferator activating receptor gamma (PPARγ) agonists, have been recognized as promising agents for memory in patients with AD. However the exact signaling mechanism remains relatively unknown. Although currently available PPARγ agonists show promise for improving memory deficits in AD, poor blood brain barrier permeability results in inadequate bio-availability in the brain requiring high dosing with chronic time frames that are associated with increased incidences of myocardial infarction. The innovation of our proposed research is based on the development of novel selective PPARγ modulators with high blood brain barrier permeability. These selective PPARγ modulators are used as tools to better understand how central PPARγ activation alters synaptic plasticity and cognition in animal models of AD without the deleterious side effects on the heart. We have identified a novel signaling mechanism in which PPARγ transcriptionally regulates an increase in expression of the neurotrophin BDNF, which is known to induce synaptogenesis and improve memory consolidation. Although our preliminary data in which our lead compound improves memory deficits and increases post synaptic receptor expression is in a diabetic type 2 (db/db) mouse model will extend these findings into a 3xTg-Ad mouse model in the current proposal. Our central hypothesis will test that our lead compound improves cognitive deficits and pathologies associated from Alzheimer's disease better than current TZDs in a 3x Tg-AD mouse with the following aims: (compound 9) 1. To compare the beneficial effects of compound 9 to Pio on improving memory deficits and synaptic plasticity in the 3xTg-AD mouse. 2. To evaluate possible mechanisms for how compound 9 rescues cognitive deficits and pathologies vs Pio. We expect that further evaluation of these compounds will lead to increased knowledge base for identifying molecular targets that will ameliorate memory deficits associated with AD. Findings from this study will advance the knowledge base and beneficial mechanistic insights into PPARγ modes of action against AD.

描述（由申请人提供）：阿尔茨海默病（AD）是美国的主要死亡原因之一，表明缺乏预防疾病进展的治疗方法。由于AD导致的死亡率的持续增加表明迫切需要发现新的药物，并进一步建立对具有治疗潜力的新分子靶点的需求。许多报告证实了AD和糖尿病之间的直接病理联系，这突出了糖尿病对AD发展的贡献。噻唑烷二酮类药物（TZDs）是一种胰岛素增敏性过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，被认为是改善AD患者记忆的有效药物。然而，确切的信号传导机制仍然相对未知。尽管目前可用的PPARγ激动剂显示出改善AD中记忆缺陷的前景，但血脑屏障通透性差导致脑中生物利用度不足，需要高剂量的慢性时间范围，与心肌梗死的发病率增加有关。我们提出的研究创新是基于开发具有高血脑屏障通透性的新型选择性PPARγ调节剂。这些选择性的PPARγ调节剂被用作工具，以更好地了解中央PPARγ激活如何改变AD动物模型中的突触可塑性和认知，而不会对心脏产生有害的副作用。我们已经确定了一种新的信号传导机制，其中PPARγ转录调节神经营养因子BDNF表达的增加，这是已知的诱导突触发生和改善记忆巩固。虽然我们的先导化合物在2型糖尿病（db/db）小鼠模型中改善记忆缺陷并增加突触后受体表达的初步数据将在当前提议中将这些发现扩展到3xTg-Ad小鼠模型中。我们的中心假设将测试我们的先导化合物在3x Tg-AD小鼠中比目前的TZD更好地改善认知缺陷和与阿尔茨海默病相关的病理，目的如下：比较化合物9与Pio对改善3xTg-AD小鼠的记忆缺陷和突触可塑性的有益作用。2.评价化合物9相对于Pio如何挽救认知缺陷和病理的可能机制。我们期望对这些化合物的进一步评估将导致增加用于识别将改善与AD相关的记忆缺陷的分子靶点的知识基础。这项研究的结果将推进知识基础和有益的机制见解的PPARγ对AD的作用模式。