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The functional role of FLAP in Alzheimer's Disease

FLAP 在阿尔茨海默病中的功能作用

基本信息

批准号：
8309154
负责人：
DOMENICO PRATICO
金额：
$ 19.13万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309154
关键词：
Ablation Affect Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Amyloidosis Animal Model Animals Arachidonate 5-Lipoxygenase Area Behavioral Biochemical Biological Brain Brain Diseases Brain Pathology Cerebellum Clinical Cognition Complex Critiques Data Deposition Development Disease Dose Elderly Enzymes Evaluation Future Genetic Goals Hippocampus (Brain)Human In Vitro Individual Investigation Lead Lipoxygenase MK 0591 Membrane Proteins Molecular Target Mus Nerve Degeneration Neuraxis Neurobiology Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Protein Inhibition Proteins Publishing Regimen Research Design Risk Factors Role Staging Study Section Testing Tg2576 Therapeutic Transgenic Mice Transgenic Organisms United States Food and Drug Administration Update Writing amyloid pathology base behavioral impairment clinical Diagnosis cognitive function comparative efficacy drug candidate efficacy testing enzyme activity improved in vivo inhibitor/antagonist interest meetings mild neurocognitive impairment mind control mouse model neuropathology new therapeutic target novel novel therapeutics pre-clinical prevent programs research clinical testing therapeutic target transgenic model of alzheimer disease

项目摘要

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.

描述（由申请人提供）：本提案的范围是开发一种新的临床前治疗策略，候选药物用于未来的临床试验，以治疗或预防阿尔茨海默病（AD）。5-脂氧合酶（5-Lipoxygenase，5LO）是一种在中枢神经系统（CNS）中大量存在的酶，其激活依赖于一种称为FLAP（5-LO activating protein，5-LO激活蛋白）的膜相关蛋白。在大脑中，FLAP依赖性5LO激活随着年龄的增长而增加，这是发展AD的最强风险因素之一。有趣的是，这些水平在AD大脑中甚至比对照组更高。另一方面，最近我们已经表明，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）水平的显著降低。总之，这些数据表明该途径参与AD发病机制，并支持我们的中心假设：FLAP/5LO酶途径在AD的发展中起着功能性作用，其药理学调节代表了一种新的AD治疗靶点。这项原理验证研究的目的是验证FLAP作为AD神经生物学中一种新的功能重要的分子靶点。通过这种临床前类型的研究，我们希望验证FLAP药理学抑制将改善AD转基因小鼠模型的AD样神经病理学和行为缺陷的假设。为了实现这一目标，我们将使用一种选择性FLAP抑制剂，即MK-591，在以下具体目标：具体目标1：测试的假设，早期FLAP药理学抑制将延迟和/或防止AD样神经病理学和行为缺陷的发展在年轻的APP转基因小鼠。具体目标二：在建立AD样神经病理学和行为缺陷后，评估APP转基因小鼠中FLAP药理学抑制的功效。通过这些研究，我们打算完成FLAP抑制剂作为AD潜在治疗药物的临床前开发的初始步骤。如果我们证明MK-591给药导致脑淀粉样变性的调节（减少），并改善该AD模型中的行为障碍，我们的发现将代表后续更全面的项目提交的生物学基础（即，UO 1），其中将测试几种不同的FLAP抑制剂并比较其在该AD模型以及其他AD模型中的功效。作为这项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）和测试任何已确定的先导化合物在临床诊断为轻度认知障碍（MCI）和AD的个体中的应用。这些研究如果成功，最终可能会导致向美国食品和药物管理局（FDA）申请研究新药（IND）。