The functional role of FLAP in Alzheimer's Disease

描述(由申请人提供)：这项建议的范围是开发一种新的临床前治疗策略，并开发一种候选药物，用于未来的临床测试，以治疗或预防阿尔茨海默病(AD)。AD影响着全球越来越多的人，而且没有治愈的方法。5-脂氧合酶(5-LO)是一种广泛存在于中枢神经系统(CNS)中的酶，其激活依赖于一种膜相关蛋白--5-LO激活蛋白(5-LO激活蛋白)的存在。在大脑中，依赖于瓣的5LO活性随着年龄的增长而增加，这是发展为阿尔茨海默病的最强风险因素之一。有趣的是，与对照组相比，阿尔茨海默病患者大脑中的这些水平甚至更高。另一方面，最近我们发现，在AD动物模型中，5LO酶活性的遗传缺失导致淀粉样蛋白2(A2)水平显著降低。综上所述，这些数据提示该途径参与了AD的发病机制，并支持我们的中心假说：Flat/5LO酶途径在AD的发生发展中发挥着功能作用；其药理调节代表了AD治疗的新靶点。这项原则验证研究的目的是验证FLOW作为AD神经生物学中一个新的和功能上重要的分子靶点。通过这种临床前类型的研究，我们想要检验这样的假设，即药物抑制将改善转基因AD小鼠模型的AD样神经病理和行为缺陷。为了实现这一目标，我们将在以下特定目的中使用选择性翻盖抑制剂MK-591：特定目的1：验证早期翻盖药物抑制将延缓和/或防止年轻APP转基因小鼠AD样神经病理和行为缺陷的发展的假说。具体目的2：在APP转基因小鼠建立AD样神经病理和行为缺陷后，评估其药物抑制的疗效。通过这些研究，我们打算完成作为AD潜在治疗药物的瓣膜抑制剂临床前开发的第一步。如果我们证明，在这个AD模型中，MK-591给药导致大脑淀粉样变性的调节(减少)和行为障碍的改善，我们的发现将代表后续更全面的项目提交(即，UO1)的生物学基础，其中将测试和比较几种不同的瓣膜抑制剂在该AD模型和其他AD模型中的有效性。作为这一未来研究计划的一部分，我们还将专注于临床前优化(剂量、疗效)和对临床诊断为轻度认知障碍(MCI)和阿尔茨海默病(AD)的患者进行任何已确定的先导化合物的测试。如果这些研究成功，最终可能导致对新药(IND)申请向美国食品和药物管理局(FDA)进行调查。 与公共卫生相关：阿尔茨海默病(AD)是一种脑部疾病，会导致认知功能的急剧丧失，并影响全球数百万老年人。然而，其病因(S)仍不清楚，也没有治愈的方法。5-脂氧合酶激活蛋白是AD重要的酶途径中不可或缺的一部分，其水平在AD时较对照组升高，因此可能直接参与AD的发生发展。MK-591是一种有效的、特异的和选择性的口服活性药物，可以阻断皮瓣并阻止这一酶途径的激活。通过这些原则验证研究，我们想要测试翻转是预防和/或治疗AD的新靶点。为此，我们将在AD转基因小鼠模型中应用MK-591，并寻找其对脑病理(淀粉样β蛋白水平和沉积)以及这些动物的行为缺陷的潜在有益影响。如果我们证明一种瓣膜抑制剂可以改善这些小鼠的表型，我们的发现将为将来用这类药物治疗阿尔茨海默病提供生物学基础。 免责声明：请注意，以下批评是由评审员在研究小组会议之前准备的，基本上是以未经编辑的形式提供的。虽然审查员有机会根据小组的讨论更新或修订其书面评价，但不能保证在会议讨论之后更新了个别批评意见。因此，这些评论可能不能完全反映个别评审员在小组讨论结束时的最终意见或小组的最终多数意见。因此，讨论纪要和总结是审查员在会议上实际上认为至关重要的最后结论。

DESCRIPTION (provided by applicant): The scope of this proposal is to develop a novel pre-clinical therapeutic strategy with a candidate drug for future clinical testing to treat or prevent Alzheimer's disease (AD). AD affects a growing number of individuals worldwide and there is no cure for it. 5-Lipoxygenase (5LO) is an enzyme abundantly present in the central nervous system (CNS), where its activation depends on the presence of a membrane associated protein called FLAP (5-LO activating protein). In the brain, FLAP-dependent 5LO activation increases with aging, one of the strongest risk factors for developing AD. Interestingly, these levels are even higher in AD brains compared with controls. On the other hand, recently we have shown that genetic absence of 5LO enzymatic activity results in a significant reduction of Amyloid 2 (A2) levels in an animal model of AD. Taken together these data suggest an involvement of this pathway in the AD pathogenesis, and support our central hypotheses: FLAP/5LO enzymatic pathway plays a functional role in AD development; its pharmacological modulation represents a novel AD therapeutic target. The objective of this proof-of-principle study is to validate FLAP as a novel and functionally important molecular target in the neurobiology of AD. With this pre-clinical type of studies we want to test the hypothesis that FLAP pharmacological inhibition will ameliorate the AD-like neuropathology and behavioral deficits of a transgenic mouse model of AD. To achieve this goal, we will use a selective FLAP inhibitor, i.e. MK-591, in the following specific aims: Specific Aim 1: Test the hypothesis that early FLAP pharmacological inhibition will delay and or prevents the development of AD-like neuropathology and behavioral deficits in young APP transgenic mice. Specific Aim 2: Assess the efficacy of FLAP pharmacological inhibition in APP transgenic mice after the AD-like neuropathology and behavioral deficits are established. With these studies we intend to complete the initial step in the pipeline for the pre-clinical development of FLAP inhibitors as potential therapeutics for AD. If we demonstrate that MK-591 administration results in a modulation (decrease) of brain amyloidosis, and improvement of behavioral impairments in this AD model, our findings will represent the biologic basis for a subsequent and more comprehensive project submission (i.e., UO1) where several different FLAP inhibitors will be tested and compared for efficacy in this as well as in other AD models. As part of this future research program we will also focus on the pre-clinical optimization (doses, efficacy) and testing of any of the identified lead compounds in individuals with a clinical diagnosis of mild cognitive impairment (MCI) and AD. These studies, if successful, could ultimately lead to an investigation new drug (IND) application to the Food and Drug Administration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a disorder of the brain that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. However, its causes(s) remain unknown and there is no cure for it. Five-Lipoxygenase Activating Protein (FLAP) is an indispensable part of an important enzymatic pathway whose levels are increased in AD when compared with control brains, and for this reason it could be directly involved in the development of the disease. MK-591 is a potent, specific and selective drug orally active that blocks FLAP and prevents the activation of this enzymatic pathway. With these proof-of-principle studies we want to test that FLAP is a novel target for AD prevention and/or treatment. To this end, we will administer MK-591 to a transgenic mouse model of AD and look for its potential beneficial effects on brain pathology (amyloid beta levels and deposition) as well as behavioral deficits in these animals. If we prove that a FLAP inhibitor ameliorates the phenotype of these mice, our findings will provide the biological basis for future human studies with this class of drugs in AD. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.