Novel Mechanisms of NSAID Action in Alzheimer's Disease

NSAID 治疗阿尔茨海默病的新机制

• 批准号: 7563358
• 负责人: EDWARD H. KOO
• 金额: $ 152.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563358
• 关键词: Novel; Mechanisms; NSAID; Action; Alzheimer

DESCRIPTION (provided by applicant): This proposal is for a five year renewal (years 6-10) of a Program Project to pursue gamma-secretase modulating compounds as Alzheimer's disease (AD) therapeutics at the University of California, San Diego, consortium with Mayo Clinic Jacksonville and Washington University, St Louis. In the first five years of support, we have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have a novel secondary action that modulates gamma-secretase processing in a cyclooxygenase (COX) independent manner. The activity of a subset of NSAIDs preferentially lowers the amyloidogenic A¿42 peptide both in vitro and in vivo, leading us to propose that this activity may be one explanation for the apparent risk reduction of AD in chronic NSAID users. As we have identified many compounds in addition to NSAIDs that shift gamma secretase cleavage, we now generically refer to these compounds as gamma-secretase modulators (GSMs). Our research efforts have contributed to the introduction of the first GSM, R-flurbiprofen ("Flurizan" renamed Tarenflurbil") into the clinic for testing in AD treatment, and led to the preclinical development of additional GSMs. The two major goals of this PPG are to further understand the mechanism of action of GSMs, and to test their activity in humans as well as determine their ability to lower disease-associated biomarkers in AD individuals. Project 1 will examine the site of action of GSMs with respect to effects on gamma- versus epsilon-cleavage and test the efficacy of combination treatments in rodents. Project 2, which has now incorporated the former Chemistry Core, will extend studies relating to the binding site of multiple GSMs, examine the relative contribution of GSMs with respect to reducing A¿42 production vs. inhibiting A¿ aggregation, and conduct animal studies to better define how GSMs acutely alter A¿ levels in the brain, CSF, and plasma of mouse AD models. Projects 1 and 2 will coordinately examine the biological properties of shorter A¿ peptides which are elevated by these GSMs. Project 3 will determine if R-flurbiprofen lowers A¿42 in human CSF by measuring newly synthesized A¿ through in-dwelling catheter and will test whether a GSM (ibuprofen) will reduce disease associated CSF biomarkers and brain volumetric changes by neuroimaging in AD subjects in a one year placebo controlled double-blind treatment study. Successful completion of these studies will provide greater insight into 1) how the GSMs shift gamma cleavage, 2) how GSMs attenuate AD-like phenotypes in rodent models, and 3) how GSMs and GSM based NSAIDs may work in humans. By providing additional preclinical and clinical information on GAMs, such studies should contribute significantly to the further development of GSMs as Alzheimer's therapeutics. PRINCIPAL INVESTIGATOR: Dr. Edward Koo is a world renowned and experienced AD research. He is well qualified to lead this program project. REVIEW OF INDIVIDUAL COMPONENTS CORE A - Administrative Core, Dr. Edward Koo DESCRIPTION (provided by applicant): The responsibilities of the Administrative Core are to coordinate and integrate the activities of the three Projects to ensure maximum cooperation and coordination of efforts among program investigators. Further, the Core will provide administrative and financial support for the Projects on an ongoing basis. The Core will organize the annual visit of the External Advisory Committee to review the scientific progress of the Projects. The Core will interface with the Data Safety and Monitoring Board who will oversee the safety aspects of the clinical studies proposed in Project 3. Further, the Core will provide fiscal and management oversight of the Alzheimer's Disease Cooperative Study (ADCS) who will be directing the biomarkers study proposed in Project 3. Another goal of the Core is to enrich aging and Alzheimer's disease research by facilitating the dissemination of results and interaction with other investigators at UCSD, Mayo Clinic Jacksonville, and other local institutions. The Administrative Core is responsible for assuring compliance with animal welfare, scientific integrity, and financial policy requirements of UCSD and NIH. Lastly, the Core will be responsible to assembling the annual progress report to NIH.

描述（由申请人提供）：本提案旨在对加州大学圣地亚哥分校与梅奥诊所杰克逊维尔分校和圣路易斯华盛顿大学联合开展的项目进行五年更新（第 6-10 年），以寻求伽马分泌酶调节化合物作为阿尔茨海默病 (AD) 的治疗方法。在支持的前五年中，我们已经证明非甾体类抗炎药 (NSAID) 具有一种新颖的次级作用，可以以不依赖环氧合酶 (COX) 的方式调节 γ-分泌酶加工。一部分 NSAID 的活性在体外和体内均优先降低淀粉样蛋白 A¿42 肽，因此我们提出这种活性可能是长期 NSAID 使用者 AD 风险明显降低的一种解释。由于我们已经鉴定出除 NSAID 之外的许多可改变 γ 分泌酶裂解的化合物，因此我们现在将这些化合物统称为 γ 分泌酶调节剂 (GSM)。我们的研究工作有助于将第一个 GSM R-flurbiprofen（“Flurizan”更名为 Tarenflurbil“）引入临床用于 AD 治疗测试，并导致其他 GSM 的临床前开发。该 PPG 的两个主要目标是进一步了解 GSM 的作用机制，测试其在人类中的活性以及确定其降低 AD 个体中疾病相关生物标志物的能力。项目 1将检查GSM的作用位点对γ-与ε-裂解的影响，并测试啮齿动物中联合治疗的功效。项目 2 现已纳入前化学核心，将扩展与多个 GSM 结合位点相关的研究，检查 GSM 在减少 A¿42 产生与抑制 A¿ 聚集方面的相对贡献，并进行动物研究以更好地确定如何 GSM 会急剧改变小鼠 AD 模型的大脑、脑脊液和血浆中的 A 水平。项目 1 和 2 将协调检查这些 GSM 增强的较短 A¿ 肽的生物学特性。项目 3 将通过留置导管测量新合成的 A¿，确定 R-氟比洛芬是否降低人脑脊液中的 A¿42，并将测试 GSM（布洛芬）是否 在一项为期一年的安慰剂对照双盲治疗研究中，将通过 AD 受试者的神经影像学来减少与疾病相关的 CSF 生物标志物和脑体积变化。这些研究的成功完成将更深入地了解 1) GSM 如何改变伽玛裂解，2) GSM 如何减弱啮齿动物模型中的 AD 样表型，以及 3) GSM 和基于 GSM 的 NSAID 如何在人类中发挥作用。通过提供额外的 凭借有关 GAM 的临床前和临床信息，此类研究将为 GSM 作为阿尔茨海默病治疗药物的进一步发展做出重大贡献。 首席研究员：Edward Koo 博士是一位世界知名且经验丰富的 AD 研究人员。他完全有资格领导该计划项目。 个别组件的审查 核心 A - 行政核心，Edward Koo 博士 描述（由申请人提供）： 行政核心的职责是协调和整合三个项目的活动，以确保项目研究人员之间最大限度的合作和协调。此外，核心将为这些项目持续提供行政和财务支持。核心将组织外部顾问委员会每年进行一次访问，以审查项目的科学进展。该核心将与数据安全和监测委员会对接，该委员会将监督项目 3 中提出的临床研究的安全方面。此外，该核心将为阿尔茨海默氏病合作研究 (ADCS) 提供财务和管理监督，该合作研究将指导项目 3 中提出的生物标志物研究。该核心的另一个目标是通过促进结果的传播和与研究人员的互动来丰富衰老和阿尔茨海默氏病的研究。 加州大学圣地亚哥分校、杰克逊维尔梅奥诊所和其他当地机构的其他研究人员。行政核心负责确保遵守 UCSD 和 NIH 的动物福利、科学诚信和财务政策要求。最后，核心将负责向 NIH 编写年度进展报告。