NEURAL PROTEASES--NEW ALZHEIMER'S DISEASE DRUG TARGETS

我们建议成立一个治疗认知障碍的药物发现小组 阿尔茨海默病相关损害(DDG-AD)。总目标 是确定介导致病分子事件的靶点 阿尔茨海默病(AD)，并开发治疗AD的潜在候选药物。 这次DDG-AD的重点将是发现独特的神经蛋白酶 介导AD异常和致病过程的酶，以及 这些蛋白水解酶的抑制剂作为治疗AD的药物的发展。这个DDG-AD 将是一项高度协作的工作，集成了许多学科，包括 从化学、生物化学和结构生物物理学，到分子和 细胞神经生物学、免疫诊断学、转基因和行为学 神经药理学。为了实现这一计划的总体目标， 我们计划开展六个科学项目。在项目1中，探测 分子将被设计成识别目标神经蛋白酶，而 这些酶的三维结构将被解决，使 以合理结构为基础的药物设计。项目2将评估脑组织 和脑脊液来关联靶神经的存在 带有已知AD标记ADAP的蛋白水解酶。项目2也将开发 诊断性脑脊液化验有助于早期识别AD患者。 项目3将进行鉴定、提纯和 独有AD相关蛋白水解酶的鉴定及检测方法的建立 评价设计的蛋白水解酶抑制剂靶向性的方法学。 项目4将利用基于分子生物学的策略来建立 阿尔茨海默病中神经蛋白酶异常参与的分子基础。项目4 还将产生DNA构建物，用于开发转基因小鼠 展示AD相关病理，用于行为研究和药物 评估。项目5将调查异常的细胞作用 神经蛋白水解酶在淀粉样前体蛋白加工中的作用 其他神经元过程，并将评估蛋白酶的影响 这些过程中的抑制剂。项目6将建立分子 截断神经生长因子受体的基础，包括 确定负责的蛋白酶(S)，并调查其作用 这一过程与AD相关的神经退行性变有关。这六个项目将是 目标蛋白水解酶的来源组织，并作为 疾病状态(正常、AD或非AD)的精确临床识别 痴呆症)。核心C将提供蛋白质等生物技术支持 测序，核苷酸测序和合成，以及生产 单克隆抗体。核心D将支持产生转基因基因的努力 “阿尔茨海默病小鼠”，并与 项目1、3、4和6。核心F将为 评估潜在的候选缓蚀剂，并对 转基因小鼠。这项计划的主要研究重点将是 然而，靶标识别和抑制剂设计，实质上是药用 化学和相关活动将由雅培公司在 加快开发临床候选药物的适当时间 广告。

We propose to form a Drug Discovery Group For the Treatment of Cognitive Impairment Associated with Alzheimer's Disease (DDG-AD). The overall goal is to identify targets that mediate pathogenic molecular events in Alzheimer's Disease (AD), and develop potential drug candidates for AD. The focus of this DDG-AD will be the discovery of distinct neural protease enzymes that mediate abnormal and pathogenic processes in AD, and the development of inhibitors of these proteases as drugs for AD. This DDG-AD will be a highly collaborative effort, integrating many disciplines ranging from chemistry, biochemistry and structural biophysics, to molecular and cellular neurobiology, immunodiagnostics, transgenics and behavioral neuropharmacology. In order to achieve the overall goals of this program, we propose to carry out six scientific projects. In Project 1, probe molecules will be designed to identify target neural proteases, and the three-dimensional structure of these proteases will be solved, enabling rational structure-based drug design. Project 2 will evaluate brain tissue and cerebrospinal fluid to correlate the presence of target neural proteases with the known AD marker, ADAP. Project 2 also will develop diagnostic CSF assays to enable early identification of AD patients. Project 3 will carry out the identification, purification and characterization of unique AD-associated proteases, and establish assay methodology to evaluate target efficacy of designed protease inhibitors. Project 4 will utilize molecular biology-based strategies to establish the molecular basis of abnormal neural protease involvement in AD. Project 4 also will generate DNA constructs for development of transgenic mice that exhibit AD-associated pathology, for use in behavioral studies and drug evaluation. Project 5 will investigate the cellular role of abnormal neural proteases in the processing of amyloid precursor protein, and in other neuronal processes, and will assess the effects of protease inhibitors on these processes. Project 6 will establish the molecular basis for truncation of the nerve growth factor receptor, including the identification of the responsible protease(s), and investigate the role of this process in AD-related neurodegeneration. The six projects will be source tissue for target proteases, and serve as a reference resource for precise clinical identification of disease state (normal, AD, or non-AD dementia). Core C will provide biotechnology support such as protein sequencing, nucleotide sequencing and synthesis, and production of monoclonal antibodies. Core D will support efforts to generate transgenic "Alzheimer's mice", and evaluate their pathology, in collaboration with Projects 1, 3, 4 and 6. Core F will provide neuropharmacology support to evaluate potential inhibitor candidates, and behavioral evaluation on transgenic mice. The primary research emphasis of this program will be target identification and inhibitor design, however, substantial medicinal chemistry and related activities will be mobilized by Abbott at the appropriate time to expedite development of a clinical drug candidate for AD.