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

基本信息

批准号：
8662606
负责人：
TAKESHI SAKURAI
金额：
$ 24.6万
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：
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/8662606
关键词：
Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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 在阿尔茨海默病中发挥着核心作用¿它被裂解产生 AB，这是 AD 中观察到的淀粉样斑块的主要成分。裂解还产生 APP (AICD) 的细胞内区域，与其相互作用的蛋白质（如 Fe65）一起进入细胞核。我们最近的研究发现 Fe65 与 Teashirt (Tsh) 蛋白相互作用，并共同沉默基因组的基因表达。我们还发现 Fe65 和 Tsh3 的表达甚至降低。此外，遗传关联研究发现 TSHZ3 的保护性等位基因编码与 Tsh3 较高表达相关的基因。最后，受 Fe65-Tsh3 调节的基因之一是 CASP4（一种 caspase-4 基因）。，一种灵长类特异性炎症半胱天冬酶，也随着 AD 进展而上调。这些结果导致我们假设 APP-Fe65-Tsh 通路抑制基因的表达，例如caspase-4 可以防止 AD 进展，并且该通路的去抑制有助于 AD 发病机制。由于 CASP4 是灵长类动物特异性的，因此我们将引入人类 caspase。 -4基因导入小鼠并在啮齿动物中重建Fe65-Tshcaspase-4通路，并通过将小鼠与AD模型小鼠（APP/PSEN双基因小鼠）杂交来阐明其在AD进展中的参与。将 Tshz3 杂合子与 APP/PSEN 双基因小鼠杂交，以阐明 Tsh3 对 AD 病理进展的保护作用。我们将使用死后脑样本将这些小鼠的 AD 进展模式与人类进行比较，通过这些分析，我们将识别和验证分子途径。参与 AD 进展，可能是潜在的治疗靶点。