Ligand discovery for delineating cholesterol homeostasis in the brain

项目摘要：PI和他在埃默里大学的调查团队旨在建立一个富有成效的合作研究 平台，并在日本主办机构（NIRS/QST）获得先进的研究技能，以支持进步 美国国立卫生研究院通过美国-日本脑研究合作计划（BRCP）的母基金。 阿尔茨海默病（AD）是一种长期的神经退行性疾病，在所有疾病的主要病因中排名第六。 在美国的死亡和特征淀粉样β蛋白沉积和神经系统缠结。目前有 没有药物可以阻止或逆转疾病的进展，所有创造这种疗法的努力都失败了。最近 研究表明，脑中胆固醇稳态的异常与 几种神经退行性疾病，包括AD。CYP 46 A1将脑胆固醇酶促转化为24 S- 羟基胆固醇是维持脑胆固醇稳态的主要消除机制。扰动 CYP 46 A1与AD的病理生理学有关。因此，CYP 46 A1的药理学调节代表了 有吸引力的AD治疗方法。正电子发射断层扫描（PET）能够定量生化 合适的CYP 46 A1配体将大大提高我们对CYP 46 A1 - 3的理解。 在AD病理生理条件下介导的胆固醇稳态，否则离体 （破坏性）分析。通过PET定量活体AD脑中的CYP 46 A1将提供以下评估： 新AD治疗剂的分布、靶点接合和剂量占用。到目前为止，还没有成功的例子。 已被证明可以对CYP 46 A1进行成像以供临床使用，这代表了我们研究这一问题的能力的重大不足。 体内靶向。因此，我们建议开发一种新的PET配体，可以填补这一空白，作为第一个翻译 AD的成像工具。 通过美国的行政补充-日本脑研究合作计划，我们将实现 我们的目标是通过以下目标：（1）在PET的发展中进行合作研究活动 中枢神经系统中靶向CYP 46 A1的配体及其在阿尔茨海默病中的意义 （2）提供一个培训平台，以获得先进的研究技能，如放射化学和 PET成像研究，在日本主办机构（NIRS/QST），可以大大受益于我们现有的母公司 研究;（3）在埃默里大学之间建立富有成效和可持续的工作关系和科学对话 和NIRS/QST继续在与NIA使命一致的共同感兴趣的研究课题上进行合作。

Project Abstract: The PI and his investigation team at Emory aim to establish a productive and collaborative research platform and acquire advanced research skills in Japanese host institution (NIRS/QST) to support the advancement of the parent NIH award through the US-Japan Brain Research Cooperative Program (BRCP). Alzheimer’s disease (AD) is a long-term neurodegenerative disorder that ranks sixth in the leading cause of all deaths in the United States and features amyloid β protein deposition and neurofibrillary tangles. At present, there are no drugs available to halt or reverse disease progression, and all efforts to create such therapies have failed. Recent studies have demonstrated that abnormalities of cholesterol homeostasis in the brain are strongly associated with several neurodegenerative diseases, including AD. The CYP46A1 enzymatic conversion of brain cholesterol into 24S- hydroxycholesterol is the major elimination mechanism to maintain brain cholesterol homeostasis. Disturbances in CYP46A1 is implicated in the AD physiopathology. Therefore, pharmacological modulation of CYP46A1 represents an attractive AD therapeutic approach. Positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable CYP46A1 ligand would substantially improve our understanding of CYP46A1- mediated cholesterol homeostasis under AD physiopathological conditions otherwise inaccessible by ex vivo (destructive) analysis. Quantification of CYP46A1 in living AD brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new AD therapeutics. To date, no successful examples have been demonstrated to image CYP46A1 for clinical use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool for AD. Through the administrative supplements for the U.S.-Japan Brain Research Cooperative Program, we will achieve our goals through the following objectives: (1) To conduct collaborative research activities in the development of PET ligands targeting CYP46A1 in the central nervous system and its implication in Alzheimer’s disease as the focus of PI’s parent award; (2) To provide a training flatform to acquire advanced research skills, such as radiochemistry and PET imaging studies, in the Japanese host institution (NIRS/QST) that could substantially benefit our existing parent research; and (3) To establish a productive and sustainable working relationship and scientific dialog between Emory and NIRS/QST for continued collaboration on mutually interested research topics that aligned with the NIA mission.