FE65-TSH-MEDIATED REGULATION OF GENE EXPRESSION IN ALZHEIMER'S DISEASE

FE65-TSH 介导的阿尔茨海默病基因表达调节

• 批准号: 8440871
• 负责人: TAKESHI SAKURAI
• 金额: $ 29.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8440871
• 关键词: Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animal Model; Animals; Autopsy; Behavioral; Biological; Brain; CASP4 gene; Caspase; Cell Nucleus; Cleaved cell; Disease; Disease Progression; Disinhibition; Funding; Gene Expression; Gene Expression Regulation; Genes; Heterozygote; Human; Inflammatory; Intervention; Laboratories; Lead; Mediating; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Nuclear; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Play; Primates; Production; Proteins; Regulation; Regulatory Pathway; Research; Risk Factors; Rodent; Rodent Model; Role; Sampling; Senile Plaques; Staging; System; Technology; Testing; Transgenic Mice; Transgenic Organisms; Up-Regulation; base; follow-up; genetic association; human CASP4 protein; in vivo; mouse model; neuroinflammation; neuropathology; protective effect; reconstitution; therapeutic target

APP plays central roles in Alzheimer¿s disease (AD) pathogenesis. It is cleaved to produce AB that is a major component of amyloid plaque observed in AD. The cleavage also produces intracellular region of APP (AICD) that, together with its interacting proteins such as Fe65, goes to nucleus where it regulates gene expression. Our recent study identified that Fe65 interacts with Teashirt (Tsh) protein, and together silence gene expression of sets of genes. We also found that expression of Fe65 and Tsh3 is decreased even in early stage of AD. Furthermore, genetic association studies identified protective alleles for TSHZ3 that encodes a gene for Tsh3 that are associated with higher expression of Tsh3. Finally, one of genes regulated by Fe65-Tsh3 is CASP4, a gene for caspase-4, a primate specific inflammatory caspase, which also show upregulation with AD progression. These results lead to our hypothesis that APP-Fe65-Tsh pathway suppresses expression of genes, such as caspase-4 and by doing so, protects against AD progression, and that disinhibition of this pathway contributes to AD pathogenesis. In the current proposal, we will test our hypothesis by using animal models. Since CASP4 is primate specific, we will introduce human caspase-4 gene into mice and reconstitute Fe65-Tshcaspase-4 pathway in rodent, and clarify its involvement in AD progression by crossing the mice with AD model mice (APP/PSEN bigenic mice). We will also cross Tshz3 heterozygotes with APP/PSEN bigenic mice to clarify protective effects of Tsh3 to progression of AD pathology. We will compare AD progression patterns in these mice with those in humans using postmortem brain samples. Through these analyses, we will identify and validate molecular pathway that is involved in AD progression, which can be a potential therapeutic target.

App在阿尔茨海默氏病（AD）发病机理中扮演着核心作用。裂解以产生AB，这是在AD中观察到的淀粉样蛋白斑块的主要组成部分。裂解还会产生APP（AICD）的细胞内区域，并与其相互作用的蛋白（例如Fe65）一起进入调节基因表达的核。我们最近的研究表明，Fe65与茶水（TSH）蛋白质相互作用，并将一组基因的基因表达在一起。我们还发现，即使在AD的早期，FE65和TSH3的表达也是高级的。此外，遗传关联研究确定了TSHZ3的受保护等位基因，该等位基因编码与TSH3较高表达相关的TSH3基因。最后，由Fe65-TSH3调节的基因之一是Casp4，Casp4是一种caspase-4的基因，caspase-4是一种私人特异性炎症caspase，它也随着AD进展而表现出上调。这些结果导致了我们的假设，即APP-FE65-TSH途径抑制了基因的表达，例如caspase-4，并且通过这样做可以防止AD进展，并且对该途径的抑制作用有助于AD发病机理。在当前的提案中，我们将使用动物模型检验我们的假设。由于CASP4是私有的，我们将在啮齿动物中将人caspase-4基因引入小鼠中，并重新构建Fe65-TSHCaspase-4途径，并通过用AD模型小鼠（APP/PSEN BIGENIC小鼠）跨越小鼠，从而阐明其参与AD的进展。我们还将与APP/PSEN蠕动小鼠穿越TSHZ3杂合子，以阐明TSH3对AD病理学进展的受保护作用。我们将使用验尸脑样本将这些小鼠的AD进展模式与人类中的AD进展模式进行比较。通过这些分析，我们将识别和验证与AD进展有关的分子途径，这可能是潜在的治疗靶标。