The roles of neuronal primary cilia in Alzheimer's disease

神经元初级纤毛在阿尔茨海默病中的作用

• 批准号: 10285814
• 负责人: Amal Alachkar
• 金额: $ 37.58万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285814
• 关键词: 3xTg-AD mouse; Adenylate Cyclase; Administrative Supplement; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Antibodies; Arl proteins; Axonal Transport; Behavioral; Behavioral Assay; Brain; Brain region; California; Cardiovascular Diseases; Cell division; Cell surface; Cells; Cilia; Cognitive deficits; Defect; Dementia; Dependovirus; Disease; Disease Progression; Dopamine Receptor; Drug Delivery Systems; Drug Targeting; Enterobacteria phage P1 Cre recombinase; Fenoldopam; Functional disorder; Genes; Genetic; Genetic Engineering; Goals; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; Injections; Institution; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Learning; Length; Liver diseases; LoxP-flanked allele; MAPT gene; Measures; Memory; Memory impairment; Microtubule Bundle; Microtubules; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic Deficit; Neurons; Organelles; Outcome; Pathogenesis; Pharmacology; Physiology; Play; Prefrontal Cortex; Records; Research; Role; Sensory; Serotyping; Signal Transduction; Site; Structure; Testing; Transgenes; Universities; ciliopathy; improved; mouse model; mutant; nanoparticle drug; neurotransmission; targeted treatment; 3xTg-AD mouse; Adenylate Cyclase; Administrative Supplement; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Antibodies; Arl proteins; Axonal Transport; Behavioral; Behavioral Assay; Brain; Brain region; California; Cardiovascular Diseases; Cell division; Cell surface; Cells; Cilia; Cognitive deficits; Defect; Dementia; Dependovirus; Disease; Disease Progression; Dopamine Receptor; Drug Delivery Systems; Drug Targeting; Enterobacteria phage P1 Cre recombinase; Fenoldopam; Functional disorder; Genes; Genetic; Genetic Engineering; Goals; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; Injections; Institution; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Learning; Length; Liver diseases; LoxP-flanked allele; MAPT gene; Measures; Memory; Memory impairment; Microtubule Bundle; Microtubules; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic Deficit; Neurons; Organelles; Outcome; Pathogenesis; Pharmacology; Physiology; Play; Prefrontal Cortex; Records; Research; Role; Sensory; Serotyping; Signal Transduction; Site; Structure; Testing; Transgenes; Universities; ciliopathy; improved; mouse model; mutant; nanoparticle drug; neurotransmission; targeted treatment

Project Abstract Primary cilia are mechano- and chemo-sensory organelles with diverse functions. Abnormal function or structure of primary cilia cause a list of diseases, termed ciliopathies. Although ciliopathies include expanding spectrum of kidney, liver, and cardiovascular disorders, it is yet to be investigated whether or not cilia are associated with Alzheimer’s disease (AD) and/or its related dementias. In this Administrative Supplement proposal, we combine expertise from two laboratories of the neighboring institutions. This multi-PI proposal includes Dr. Amal Alachkar (the University of California, Irvine), whose research group has strong expertise in neurological degeneration including Alzheimer, and Dr. Surya Nauli (Chapman University), whose laboratory has strong records in interrogating primary cilia functions. The overall goal of this proposal is to examine the alterations of cilia structure and functions in early- and late-stage AD in 3xTg mice brains. The role of cilia will also be evaluated using conditional inducible IFT88 knockout mice that do not possess cilia. IFT88 mouse will be put into the 3xTg-AD mouse background. Our first aim is therefore to test the hypothesis that cilia structure/length is altered in early- and/or late-stage 3xTg-AD mice. The second aim is to test the hypothesis that genetic and pharmacological manipulations of cilia alter behavioral changes in AD. The outcomes of these limited studies offer new knowledge if genetic elimination of cilia exacerbates behavioral deficits in 3xTg-AD mouse and if cilia-targeted therapy improves the behavioral deficits in 3xTg-AD mice.

项目摘要 原发性纤毛是具有不同功能的机械和化学感官细胞器。异常 原发性纤毛的功能或结构导致疾病清单，称为纤毛病。虽然 纤毛病包括扩大肾脏，肝脏和心血管疾病的范围，还没有 可以调查纤毛是否与阿尔茨海默氏病（AD）和/或相关的 痴呆症。在此行政补充建议中，我们结合了两个的专业知识 邻近机构的实验室。该多PI的建议包括Amal Alachkar博士 （加利福尼亚大学尔湾分校），其研究小组在神经学方面具有强大的专业知识 包括阿尔茨海默氏症在内的堕落和苏里亚·纳利（Surya Nauli）博士（查普曼大学）的实验室 在询问原发性纤毛功能方面有很强的记录。该提议的总体目标是 检查3XTG小鼠早期和晚期AD中纤毛结构和功能的改变 大脑。还将使用条件诱导的IFT88敲除小鼠评估纤毛的作用 没有纤毛。 IFT88鼠标将放入3XTG-AD鼠标背景中。我们的第一个 因此，目的是测试纤毛结构/长度在早期和/或晚期改变的假设 3XTG-AD小鼠。第二个目的是检验遗传和药物的假设 纤毛的操纵改变了AD的行为变化。这些有限研究的结果提供 新知识如果纤毛的遗传消除加剧了3xTG-AD小鼠的行为定义 如果以纤毛为目标的疗法可以改善3XTG-AD小鼠的行为定义。