The Idol-ApoE receptor pathway in Alzheimer's disease

项目摘要： 该申请详细介绍了一个为期五年的职业发展计划，以促进从一个 从博士后研究员到独立研究员。申请人已完成3.8年的 在洛杉矶的加州大学进行博士后培训。申请人将继续接受 博士Peter Tontonoz是脂质代谢/信号传导和相关疾病领域公认的领导者。 重要的是，Tontonoz博士已经监督了10多名博士后研究员的职业发展， 独立的学术职位，确保申请人在其指导下获得的指导质量。 继续与研究阿尔茨海默病中ApoE/Aβ代谢的专家进行互动和合作。 Jungsu Kim，马约诊所），并研究神经元和突触可塑性（博士！凯尔西马丁，加州大学洛杉矶分校和博士。 卡洛斯波特拉-卡里奥，加州大学洛杉矶分校），增加了这个应用程序的特殊优势。 阿尔茨海默病（AD）是老年人群中痴呆症的最常见原因。迄今 AD最强的遗传危险因素是载脂蛋白E（ApoE）基因型。在大脑中，ApoE的功能是 脂蛋白受体超家族成员的配体，包括低密度脂蛋白受体（LDLR）， 极低密度脂蛋白受体（VLDLR）和ApoE受体2（ApoER 2）。脑ApoE受体不 不仅强烈影响ApoE和Aβ的代谢，而且还介导 维持突触可塑性和认知功能。靶向脑ApoE受体最近出现 作为对抗AD的新治疗策略。申请人最近的研究和初步数据显示， 新型E3泛素连接酶Idol是脑ApoE受体表达的主要调节因子， 对ApoE/Aβ代谢和AD样病理的影响。在本申请中，申请人提出进一步 研究Idol可能影响AD发病机制的机制。 申请人将测试抑制脑Idol通路不仅会增加 Aβ清除和减少淀粉样蛋白负荷，但也会拮抗Aβ诱导的突触功能障碍。 使用具有全局、神经元或小胶质细胞特异性Idol缺失的转基因AD小鼠模型（APP/PS1）， 申请人将确定Idol缺乏对体内ApoE和Aβ代谢的影响，并评估 神经元和小胶质细胞的相对贡献（目标1）。此外，申请人将检验以下假设： 抑制神经元Idol将防止Aβ诱导的突触功能障碍，并探讨其潜在的作用机制。 机制（目标2）。最后，申请人将评估神经元和小胶质细胞特异性Idol缺失的影响 APP/PS1小鼠的神经病理学进展和认知功能（目的3）。 实现这一建议中的目标不仅将促进对途径的科学理解， 调节ApoE代谢和大脑中的信号传导，而且还提供了Idol潜在效用的验证 作为AD发病机制的治疗靶点。

Project Summary: This application details a five-year career development program to facilitate the transition from a mentored post-doctoral fellow to an independent researcher. The applicant has completed 3.8 years of postdoctoral training at the University of California, Los Angeles. The applicant will continue to be mentored by Dr. Peter Tontonoz, a recognized leader in the field of lipid metabolism/signaling and associated disorders. Importantly, Dr. Tontonoz has overseen the career development of over 10 post-doctoral fellows now in independent academic positions, ensuring the quality of mentoring the applicant will receive under his tutelage. Continued interaction and collaboration with experts studying ApoE/Aβ metabolism in Alzheimer’s disease (Dr. Jungsu Kim, Mayo Clinic), and studying neuronal and synaptic plasticity (Dr.!Kelsey Martin, UCLA and Dr. Carlos Portera-Cailliau, UCLA), adds particular strengths to this application. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. By far the strongest genetic risk factor for AD is apolipoprotein E (ApoE) genotype. In the brain, ApoE functions as a ligand for members of the lipoprotein receptor superfamily, including low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptors (VLDLR), and ApoE Receptor 2 (ApoER2). Brain ApoE receptors not only strongly impact the metabolism of both ApoE and Aβ, but also mediate signaling pathways required for maintaining synaptic plasticity and cognitive functions. Targeting brain ApoE receptors has recently emerged as a novel therapeutic strategy to combat AD. The applicant’s recent study and preliminary data showed a novel E3 ubiquitin ligase Idol is the major regulator of brain ApoE receptor expression, and has a profound impact on ApoE/Aβ metabolism and AD-like pathology. In this application, the Applicant proposes to further investigate the mechanisms through which Idol may impact the AD pathogenesis. The applicant will test the hypothesis that inhibiting the brain Idol pathway will not only increase Aβ clearance and reduce amyloid burden, but will also antagonize Aβ-induced synaptic dysfunction. Using transgenic AD mouse model (APP/PS1) with global, neuron-, or microglia-specific Idol deletion, the applicant will determine the effect of Idol deficiency on ApoE and Aβ metabolism in vivo, and evaluate the relative contributions from neurons and microglia (Aim 1). In addition, applicant will test the hypothesis that inhibition of neuronal Idol will prevent Aβ-induced synaptic dysfunction, and explore the underlying mechanisms (Aim 2). Finally, applicant will evaluate the impact of neuron- and microglia-specific Idol deletion to the neuropathological progression and cognitive function in APP/PS1 mice (Aim 3). Achievement of the aims in this proposal will not only further the scientific understanding of pathways modulating ApoE metabolism and signaling in the brain, but also provide validation of the potential utility of Idol as therapeutic target for AD pathogenesis.