Targeting peripheral CCR2 macrophages in traumatic brain injury

靶向外伤性脑损伤中的外周 CCR2 巨噬细胞

• 批准号: 8834690
• 负责人: Josh Morganti
• 金额: $ 5.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834690
• 关键词: Acute; Alzheimer' s Disease; Animal Model; Appearance; Blood Circulation; Brain; Brain Injuries; Brain region; CCL2 gene; CX3CL1 gene; Cell Separation; Cell Surface Receptors; Cells; Cessation of life; Chronic; Chronic Phase; Cognitive; Data; Dementia; Development; Direct Costs; Disease; Disease Progression; Environmental Risk Factor; Event; Evolution; Facilities and Administrative Costs; Foundations; Functional disorder; Future; Goals; Hippocampal Formation; Hippocampus (Brain); ITGAM gene; ITGAX gene; Image; Immune; Immune response; Impaired cognition; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Investigation; Kinetics; Knowledge; Lead; Life; Ligands; Long-Term Survivors; Measures; Mental Health; Messenger RNA; Methods; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathogenicity; Pattern; Peripheral; Phase; Phenotype; Play; Positron-Emission Tomography; Process; Production; Radial; Reporter; Risk; Role; Signal Transduction; System; Testing; Therapeutic; Time; Tissues; Trauma; Traumatic Brain Injury; United States; Veterans; Water; Work; arm; base; chemokine receptor; cognitive function; controlled cortical impact; disability; genetic manipulation; injured; insight; macrophage; monocyte; neuroinflammation; neuropathology; neurotoxic; new therapeutic target; novel; prevent; public health relevance; response; response to injury; treatment effect

DESCRIPTION (provided by applicant): Each year in the United States, at least 1.7 million people suffer traumatic brain injury (TBI); it is a contributing factor in 33% of all injury-relate US deaths. An estimated 3.2 to 5.3 million people live with the long-term physical, cognitive, and psychological health disabilities of TBI, with annual direct and indirect costs estimated at over $80 billion. Moreover, these findings are compounded by the rapid increase in TBI cases from returning veterans of overseas deployments. It is now being recognized that TBI is a process, not an event. There is emerging evidence that this process can lead to multiple neurodegenerative disorders. Clinically, TBI is one of the most powerful environmental risk factors for the development of Alzheimer's disease and dementia. However, a molecular mechanism for this association has not been identified. Emerging evidence suggests that neuroinflammation may play a pivotal role in TBI-induced neuropathology as a result of non-specific secondary or 'bystander' injury to primarily unaffected brain regions, notably the hippocampal formation. The primary effectors of CNS neuroinflammatory response are the microglia, which act as the CNS' resident tissue macrophage. Recent work in positron emission tomography ligand imaging has shown that long-term survivors of TBI have persistent activation of this innate response for years following the initial trauma. Particularly confounding to this phenomenon is the inability to reliably distinguish resident macrophage (microglia) effects versus injury-induced infiltration of peripheral monocytes/macrophages, as upon activation, each is phenotypically indistinguishable in function and appearance. Therefore the role of these infiltrating cells in the neuropathology associated with TBI remains unclear. Aim 1: Will determine the time-related accumulation of peripherally derived CCR2 positive macrophages in the brain following TBI. Brain injury will be induced using the controlled cortical impact method on CX3CR1+/GFPCCR2+/RFP reporter mice, which allow the delineation of resident versus peripheral innate immune cells. We will examine peripheral macrophage accumulation and their inflammatory profile in the brain through a comprehensive time course spanning the acute through chronic phases following injury. Preliminary studies indicate that this model induces hippocampal-dependent cognitive dysfunction, a marked increase in CCR2 cell infiltration, as well as concomitant production of pro-inflammatory mediators. Results from this aim will examine the relationship between TBI and accumulation of peripheral macrophages and their inflammatory profile across time. Aim 2: Will determine the efficacy of targeting CCR2 pharmacologically to ameliorate TBI-induced pro- inflammatory response and ultimately cognitive dysfunction. Preliminary data suggest that targeting CCR2 positive macrophages using a novel phase-I antagonist significantly depletes peripheral macrophage accumulation following injury. Moreover, this treatment paradigm significantly decreased the expression of multiple pro-inflammatory/neurotoxic responses. As Aim will define the therapeutic basis for Aim 2, we will extend treatment paradigm to cover the peak of peripheral macrophage infiltration to examine the effects this treatment has on ameliorating TBI-induced hippocampal dependent cognitive dysfunction in the chronic phase following injury.

描述（由申请人提供）：在美国，每年至少有170万人遭受创伤性脑损伤（TBI）;它是美国所有损伤相关死亡的33%的促成因素。估计有320万至530万人患有TBI的长期身体，认知和心理健康残疾，每年的直接和间接费用估计超过800亿美元。此外，这些调查结果由于海外部署的归国退伍军人的TBI病例迅速增加而变得更加复杂。现在人们认识到TBI是一个过程，而不是一个事件。有新的证据表明，这一过程可能导致多种神经退行性疾病。在临床上，TBI是阿尔茨海默病和痴呆症发展的最强大的环境风险因素之一。然而，这种关联的分子机制尚未确定。新出现的证据表明，神经炎症可能在TBI诱导的神经病理学中发挥关键作用，这是由于对主要未受影响的脑区（特别是海马结构）的非特异性继发性或“旁观者”损伤。CNS神经炎症反应的主要效应物是小胶质细胞，其充当CNS的驻留组织巨噬细胞。正电子发射断层扫描配体成像的最新研究表明，TBI的长期幸存者在最初的创伤后数年内持续激活这种先天反应。这种现象的特别混淆是不能可靠地区分驻留巨噬细胞（小胶质细胞）效应与损伤诱导的外周单核细胞/巨噬细胞浸润，因为在激活时，每种在功能和外观上都是表型上不可区分的。因此，这些浸润细胞在与TBI相关的神经病理学中的作用仍不清楚。 目的1：将确定TBI后外周来源的CCR 2阳性巨噬细胞在脑中的时间相关积累。将使用CX 3CR 1 +/GFPCCR 2 +/RFP报告小鼠的受控皮质撞击方法诱导脑损伤，其允许描绘驻留与外周先天免疫细胞。我们将通过一个全面的时间过程，从损伤后的急性期到慢性期，研究外周巨噬细胞的积聚及其在大脑中的炎症特征。初步研究表明，该模型诱导了海马依赖性认知功能障碍，CCR 2细胞浸润显著增加，以及促炎介质的伴随产生。该目的的结果将检查TBI与外周巨噬细胞积聚及其随时间的炎症特征之间的关系。 目标二：将确定靶向CCR 2 β改善TBI诱导的促炎反应和最终认知功能障碍的功效。初步数据表明，靶向CCR 2阳性巨噬细胞使用一种新的阶段-I拮抗剂显着消耗外周巨噬细胞积累损伤后。此外，这种治疗模式显著降低了多种促炎/神经毒性反应的表达。由于Aim将定义Aim 2的治疗基础，我们将扩展治疗模式以涵盖外周巨噬细胞浸润的峰值，以检查该治疗对改善损伤后慢性期TBI诱导的海马依赖性认知功能障碍的影响。