Can Targeted NOX inhibition Prevent High Fat Diet-Induced Brain Injury?

靶向 NOX 抑制可以预防高脂肪饮食引起的脑损伤吗？

基本信息

批准号：
8775980
负责人：
ANNADORA J BRUCE-KELLER
金额：
$ 18.5万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775980
关键词：
Address Adipose tissue Alzheimer&apos s Disease Anxiety Brain Brain Injuries C57BL/6 Mouse Calculi Caring Central obesity Clinical Clinical Data Clinical Management Clinical Research Cognition Complex Data Dementia Deterioration Diet Disease Emotional Epidemiology Family Fatty acid glycerol esters Functional disorder Gliosis Glucans Homeostasis Impaired cognition Impairment Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Lead Link Maps Measures Mediating Mental Depression Metabolic Microspheres Morphology Motor Multienzyme Complexes Mus NADPH Oxidase Nervous System Physiology Neurologic Neurologic Effect Neurons Obesity Pathogenesis Patients Peripheral Physiological Physiological Processes Play Prevalence Proteins Public Health Publishing Refractory Regimen Research Design Risk Rodent Role Signal Transduction Small Interfering RNA Swimming Synapses System Testing Therapeutic Visceral Wild Type Mouse base behavior measurement cell type cerebrovascular cognitive function conditioned fear cost design improved knock-down macrophage mouse model new therapeutic target novel novel strategies prevent public health relevance remediation research study targeted delivery weight loss intervention

项目摘要

DESCRIPTION (provided by applicant): Numerous clinical studies link obesity to neurologic impairment and elevated dementia risk. While these studies are generally retrospective or epidemiologic, experimental studies also provide compelling evidence that diet-induced obesity in rodents causes significant brain injury and cognitive impairment. There are several critically important reasons why the damaging effects of obesity on brain homeostasis must be experimentally resolved. First, despite the availability of various weight-loss interventions, obesity remains stubbornly prevalent and highly refractory to clinical remediation. Secondly, notwithstanding emotional devastation and family disruption, the monetary costs of caring just for Alzheimer's patients in the US could reach a staggering 1.2 trillion by 2050. If, however, the mechanisms of diet-induced brain injury are identified, it is possible that therapeutic regimens can be developed to preserve and optimize neurologic function in the context of obesity. To address this need, this proposal describes proof-of-concept studies designed to both: 1) determine if inflammatory signaling in visceral macrophages links visceral obesity to central neurologic impairment; and 2) to test the clinical utility of a new therapeutic target - the NOX2 subunit of the macrophage NADPH oxidase complex - to promote neurologically healthy obesity. Specifically, we will test the hypothesis that the selective knock-down of macrophage NOX2 prevents the progression of peripheral obesity to neurologic impairment in mice. This hypothesis is based on our recently published data showing that when compared to wild-type mice, NOX2 knockout mice are completely protected from the adverse neurologic effects of diet-induced obesity (see Appendix 1). These experiments show that the loss of NOX2 signaling in visceral macrophages confers dramatic decreases in visceral adiposopathy and inflammation, while additional recent data reveal a significant linear relationship between NADPH oxidase activity in visceral adipose and cognitive impairment in wild-type mice. These data collectively suggest that NOX2-based signaling in visceral macrophages links visceral adiposity to sustained and progressive cascades of inflammation that trigger brain injury and dysfunction. However, NOX2 is only a single component of the NADPH oxidase system, which is a pleiotropic enzyme complex mediating variety of physiologic processes. Indeed, intact NADPH oxidase function is necessary for cognitive function, ruling out broad-based inhibition of NADPH oxidase as a therapeutic approach for obesity. Therefore, to advance this important field and optimize therapeutic potential of NADPH oxidase in obesity, we have designed proof-of-concept studies using novel mouse models and cell type-specific pharmacologic targeting strategies in which the NOX2 subunit of NADPH oxidase will be individually manipulated only in macrophages. Specific Aim 1 will determine if the selective deletion of macrophageNOX2 is sufficient to prevent high fat diet-induced neurologic injury in mice, while Specific Aim 2 will thoroughly map the clinical potential of a pharmacologic macrophage-targeted NOX2 regimen in diet-induced neurologic injury.

描述（由申请人提供）：大量临床研究将肥胖与神经系统障碍和痴呆症风险升高联系起来。尽管这些研究通常是回顾性的或流行病学的，但实验研究还提供了令人信服的证据，表明啮齿动物中饮食引起的肥胖会导致严重的脑损伤和认知障碍。必须在实验上解决肥胖对大脑体内平衡的破坏性影响的重要原因。首先，尽管有各种减肥干预措施，但肥胖仍然顽固地普遍存在，并且对临床补救症高度难治性。其次，尽管情感上的破坏和家庭破坏，但在美国，关心阿尔茨海默氏症患者的货币成本可能到2050年达到1.2万亿美元。但是，如果确定了饮食诱发的脑损伤的机制，则可以开发出治疗方案以保持治疗方案可以保留和优化神经学的功能。为了满足这一需求，该提案描述了旨在同时设计的概念证明研究：1）确定内脏巨噬细胞中的炎症信号是否将内脏肥胖症与中枢神经障碍联系起来； 2）测试新的治疗靶标的临床实用性 - 巨噬细胞NADPH氧化酶复合物的NOX2亚基 - 促进神经学健康的肥胖症。具体而言，我们将检验以下假设：巨噬细胞NOX2的选择性敲低可防止外周肥胖对小鼠神经系统障碍的发展。该假设是基于我们最近发表的数据表明，与野生型小鼠相比，NOX2基因敲除小鼠受到饮食诱导的肥胖症的不良神经系统作用的保护（请参阅附录1）。这些实验表明，内脏巨噬细胞中Nox2信号传导的丧失赋予了内脏脂肪症和炎症的急剧下降，而最近的数据揭示了内脏脂肪中NADPH氧化酶活性与野生型小鼠的NADPH氧化酶活性之间的显着线性关系。这些数据共同表明，内脏巨噬细胞中基于NOX2的信号传导将内脏肥胖与持续和进行性的炎症级联相关联，从而引发脑损伤和功能障碍。但是，NOX2只是NADPH氧化酶系统的一个组成部分，这是一种多效酶复合物，介导了各种生理过程。实际上，完整的NADPH氧化酶功能对于认知功能是必不可少的，排除了对NADPH氧化酶的广泛抑制作用，这是肥胖症的治疗方法。因此，为了促进NADPH氧化酶在肥胖症中的治疗潜力并优化肥胖症的治疗潜力，我们使用新型小鼠模型和细胞类型的药物靶向策略设计了概念验证研究，其中NADPH氧化酶的NOX2亚基只能在巨噬细胞中单独操纵。具体的目标1将确定巨噬蛋白毒素的选择性缺失是否足以防止小鼠脂肪饮食诱导的高脂肪诱导的神经系统损伤，而特定的目标2将彻底绘制饮食诱导的神经学损伤的药理学巨噬细胞靶向NOX2方案的临床潜力。