CIRCADIAN CLOCK DYSFUNCTION AS A MEDIATOR OF NEURODEGENERATION

描述（由申请人提供）：这个指导职业发展奖的目标是促进主要研究者作为研究神经变性分子机制的医生-科学家向独立过渡。这项拟议中的研究将在大卫霍尔茨曼博士的指导下进行，将研究生物钟基因作为神经元氧化应激和代谢的主要调节因子的潜在作用，并研究生物钟在神经退行性疾病中的作用。昼夜节律功能障碍是许多与年龄相关的神经退行性疾病的突出症状，包括阿尔茨海默病。然而，昼夜节律功能障碍对神经退行性疾病发病机制的影响（如果有的话）尚不清楚。在分子水平上，昼夜节律是由保守的转录机制（核心昼夜节律钟）产生的，该转录机制存在于大多数细胞中， 身体，包括神经元和神经胶质，并以24小时的周期振荡。在许多组织中，生物钟是新陈代谢、衰老和氧化应激的主要调节器，尽管这在大脑中尚未得到证实。该项目的目标是测试生物钟功能障碍有助于神经退行性疾病，特别是阿尔茨海默病的发病机制的假设。为了验证这一假设，将通过以下目的来检查主生物钟基因Bmal 1的遗传缺失对脑功能和病理学的影响：1）阐明Bmal 1敲除小鼠的神经病理学变化，并鉴定介导这些变化的生物钟调节通路中的特异性信号异常。2)使用体内微透析检查Bmal 1缺失对活体小鼠神经元代谢、氧化应激和淀粉样蛋白β调节的影响。3)在阿尔茨海默病小鼠模型中确定脑特异性Bmal 1缺失对疾病发病机制、氧化应激和淀粉样β动力学的影响拟议的实验旨在阐明生物钟功能障碍和神经退行性变之间可能的新联系，最终目标是确定与年龄相关的神经退行性疾病的新治疗靶点。该培训补助金将为主要研究者提供研究培训，这将与他在痴呆症方面的临床重点平行，并最终将为基础科学发现转化为神经退行性疾病患者的诊断和治疗策略提供一套技能。

DESCRIPTION (provided by applicant): The goal of this mentored Career Development Award is to facilitate the primary investigator's transition to independence as a physician-scientist studying the molecular mechanisms of neurodegeneration. The proposed research, which will be conducted under the mentorship of Dr. David Holtzman, will examine the potential role of circadian clock genes as master regulators of neuronal oxidative stress and metabolism, and examine the role of the circadian clock in neurodegeneration. Circadian dysfunction is a prominent symptom of many age-related neurodegenerative diseases, including Alzheimer's disease. However, the impact of circadian dysfunction on neurodegenerative disease pathogenesis, if any, is unknown. On a molecular level, circadian rhythms are generated by conserved transcriptional machinery (the core circadian clock) that is present in most cells in the body, including neurons and glia, and oscillates with a 24 hour periodicity. In many tissues, circadian clocks serve as master regulators of metabolism, aging, and oxidative stress, though this has not been demonstrated in the brain. The goal of this project is to test the hypothesis that circadian clock dysfunction contributes to the pathogenesis of neurodegenerative diseases, in particular Alzheimer's disease. In order to test this hypothesis, the effect of genetic deletionof the master circadian clock gene Bmal1 on brain function and pathology will be examined through the following aims: 1) Elucidation of neuropathology changes in Bmal1 knockout mice, and identification of specific signaling abnormalities in clock-regulated pathways which mediate these changes. 2) Examination of the effect of Bmal1 deletion on neuronal metabolism, oxidative stress, and amyloid-beta regulation in living mice using in vivo micro dialysis. 3) Determination of the impact of brain-specific Bmal1 deletion on disease pathogenesis, oxidative stress, and amyloid-beta dynamics in a mouse model of Alzheimer's disease. The proposed experiments are designed to illuminate a possible novel link between circadian clock dysfunction and neurodegeneration, with the ultimate goal of indentifying novel therapeutic targets for age-related neurodegenerative conditions. This training grant will provide the primary investigator with research training which will parallels his clinical focus in dementia, and will ultimately provide a skill set for translation of basic science discoveries into diagnostic and therapeutic strategies for patients with neurodegenerative diseases.