Ligand discovery for delineating cholesterol homeostasis in the brain

项目摘要：PI和他在埃默里的调查团队的目标是建立一个富有成效和协作的研究 在日本主办机构(NIRS/QST)建立平台并获得先进的研究技能，以支持进步 通过美日脑研究合作计划(BRCP)获得母公司NIH奖。 阿尔茨海默病(AD)是一种长期的神经退行性疾病，在所有疾病中排名第六 美国的死亡病例，以淀粉样蛋白β沉积和神经原纤维缠结为特征。目前，有以下几种 没有可用的药物来阻止或逆转疾病的发展，所有创造这种疗法的努力都失败了。近期 研究表明，大脑中胆固醇稳态的异常与 几种神经退行性疾病，包括阿尔茨海默病。CYP46A1酶促脑胆固醇转化为24S- 羟基胆固醇是维持脑内胆固醇稳态的主要清除机制。骚乱发生在 细胞色素P46A1参与了AD的生理病理过程。因此，CYP46A1的药理调节代表了 一种有吸引力的AD治疗方法。正电子发射断层扫描(PET)能够定量检测生化 体内过程，以及合适的CYP46A1配体将极大地提高我们对CYP46A1- AD生理病理条件下的介导性胆固醇稳态，否则体外无法达到 (破坏性)分析。应用正电子发射计算机断层扫描技术定量检测活体AD脑内的细胞色素P46A1 阿尔茨海默病新疗法的分布、靶参与和剂量占有率。到目前为止，还没有成功的例子 已被证实为临床使用的CyP46A1，这代表了我们研究这一点的能力的一个重大缺陷 活体靶标。因此，我们建议开发一种新型的PET配体来填补这一空白，作为第一个翻译 AD的成像工具。 通过美日脑研究合作计划的行政补充，我们将实现 我们的目标是通过以下目标：(1)开展PET开发方面的合作研究活动 中枢神经系统中靶向细胞色素P46A1的配体及其在阿尔茨海默病中的意义 PI的家长奖；(2)提供培训平台，以获得先进的研究技能，如放射化学和 在日本主办机构(NIRS/QST)进行的宠物成像研究，可能会使我们现有的父母受益良多 研究；以及(3)在埃默里和埃默里之间建立富有成效和可持续的工作关系和科学对话 以及NIRS/QST，继续就共同感兴趣的研究主题进行合作，以符合NIA的使命。

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.