The Neurobiology of 5-Lipoxygenase

5-脂氧合酶的神经生物学

基本信息

批准号：
7986934
负责人：
DOMENICO PRATICO
金额：
$ 30.75万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7986934
关键词：
Ablation Address Adrenal Cortex Hormones Affect Age Aging Alzheimer&apos s Disease Amyloid Amyloidosis Animal Model Arachidonate 5-Lipoxygenase Area Attention Behavior Behavioral Biological Brain Brain region Cell Culture System Cell Culture Techniques Cells Chronic Complex Data Dementia Deposition Development Disease Elderly Enzyme Activation Enzymes Event Evolution Exhibits Exposure to F2-Isoprostanes Family Fatty Acids Future Genetic Glucocorticoids Goals Hippocampus (Brain)Hormones Human In Vitro Individual Inflammation Inflammatory Lead Leukotrienes Link Lipid Peroxidation Lipids Lipoxygenase Lipoxygenase Inhibitors Mediating Metabolic Metabolic Pathway Molecular Morphology Mus Nerve Degeneration Neuraxis Neurobiology Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oxidants Oxidative Stress Oxygen Pathogenesis Pathology Pathway interactions Patients Peptides Persons Pharmaceutical Preparations Phenotype Play Process Production Protein Precursors Proteins Publishing Rattus Regulation Risk Factors Role Senile Plaques Signal Pathway Source Stress System Testing Tg2576 Therapeutic Therapeutic Agents Transgenic Mice Up-Regulation Wild Type Mouse Work amyloid pathology behavioral impairment cognitive function disease characteristic enzyme activity immunoreactivity improved in vivo inhibitor/antagonist lipid mediator mind control mouse model neuropathology new therapeutic target normal aging novel novel therapeutics oxidation oxidative damage prevent protein metabolism public health relevance research study response stressor tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a chronic and complex neurodegenerative disease that causes progressive loss of cognitive functions with dementia and for which there is no cure. Aging is a strong risk factor for developing AD, and dysregulated oxygen-mediated events as well as inflammatory processes are considered potential biological links between aging and the disease pathogenesis. 5-Lipoxygenases (5LO) is an enzyme that oxidizes fatty acids and thereby synthesizes inflammatory lipid mediators (leukotrienes), and lipid peroxidation products (hydroxyperoxides), both of which are also potent oxidants. This enzyme is widely expressed in the central nervous system (CNS). However, despite some circumstantial evidence suggesting that it may play a role in neurodegeneration, a definitive biological role for 5LO in the CNS has yet to be established. We recently showed that the expression levels of 5LO are increased in the CNS with aging particularly in the hippocampus, and that compared to controls this enzyme is upregulated in AD brains. We also demonstrated that genetic ablation of 5LO results in reduced endogenous A¿ levels in wild type mice, and significantly less A¿ deposits in the Tg2576 mice, a mouse model of AD-like amyloidosis. Further, in cell culture systems 5LO activation and pharmacologic inhibition results in increased and reduced A¿ formation, respectively. Together, these data provide strong support for the hypothesis that this enzymatic pathway could play a functional role in AD pathogenesis, and represent a novel therapeutic target for the disease. The main goal of the current proposal is to test the hypothesis that 5LO activation results in the formation of bioactive lipids, which in turn modulate metabolic pathways germane to the AD neuropathology. The elucidation of the molecular and cellular mechanisms whereby this enzyme system influences the production and turnover of A¿ and the metabolic fate of its precursor protein, APP, is extremely important since it could establish a novel pathway relevant to the development of AD pathology, and become a new therapeutic target. Thus, if successful, our findings will provide important clues for future studies with specific 5LO inhibitors as novel therapeutic agents for preventing or limiting the evolution and /or progression of AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a disease that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. However, its cause(s) remain unknown, and there is no cure for it. 5Lipoxygenase (5LO) is a protein whose levels and activity are increased in AD compared with healthy control brain, and could be directly involved in the development of the disease. If we prove this hypothesis, our findings will provide important information for future human studies with specific drug inhibitors of 5LO as a novel therapy for the treatment of this devastating disease.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种慢性且复杂的神经退行性疾病，会导致痴呆症认知功能的逐渐丧失，并且无法治愈。衰老是发展AD的强大危险因素，氧气介导的事件以及炎症过程被认为是衰老与疾病发病机理之间的潜在生物学联系。 5-脂氧酶（5LO）是一种氧化脂肪酸的酶，从而合成炎性脂质介质（白细胞环）和脂质过氧化产物（羟氧化物），这两种酶也是潜在的氧化物。该酶在中枢神经系统（CNS）中广泛表达。但是，它可能在神经退行性中发挥作用，这是5LO在中枢神经系统中的确定生物学作用。我们最近表明，尤其是海马中的中枢神经系统中5LO的表达水平升高，与对照组相比，该酶在AD大脑中进行了更新。我们还证明，5LO的遗传消融导致野生型小鼠的内源性A水平降低，而TG2576小鼠的A沉积物明显降低，这是AD样淀粉样变性的小鼠模型。此外，在细胞培养系统中5LO激活和药物抑制分别导致A形成增加和减少。这些数据共同为这一假设提供了强烈的支持：这种酶促途径可以在AD发病机理中起功能，并代表了该疾病的新型治疗靶点。当前建议的主要目的是检验以下假设：5LO激活导致生物活性脂质的形成，这又将代谢途径与AD神经病理学调节。阐明该酶系统会影响A检测和周转的分子和细胞机制，其前体蛋白App的代谢命运非常重要，因为它可以建立与AD病理学发展相关的新途径，并成为新的治疗靶标。如果成功的话，我们的发现将为未来的5LO抑制剂作为预防或限制AD进化和 /或进展的新型治疗剂提供重要的研究集群。公共卫生相关性：阿尔茨海默氏病（AD）是一种疾病，会导致认知功能急剧丧失，并影响全球数百万个基本人。但是，它的原因仍然未知，并且无法治愈。 5脂氧合酶（5LO）是一种蛋白质，与健康对照大脑相比，AD的水平和活性升高，并且可以直接参与疾病的发展。如果我们证明了这一假设，我们的发现将为未来的人类研究提供重要的信息，以5LO的特定药物抑制剂，作为治疗这种毁灭性疾病的新疗法。