Targeting CCR2 (CC Chemokine Receptor 2) to treat TBI

靶向 CCR2（CC 趋化因子受体 2）治疗 TBI

• 批准号: 9487892
• 负责人: CHRISTINE LINDA HSIEH
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9487892
• 关键词: Address; Adult; Affect; Aftercare; Age; Area; Behavioral; Bioinformatics; Biological Markers; Biology; Brain; Brain Injuries; CC chemokine receptor 2; Cell physiology; Cells; Cessation of life; Clinical; Cognitive; Complex; Data; Development; Diabetic Nephropathy; Dichloromethylene Diphosphonate; Disease; Dose; Expression Profiling; Functional disorder; Goals; Health; Heterogeneity; Histopathology; Human; Incidence; Infiltration; Inflammation; Injury; Innate Immune Response; Intervention; Kidney Diseases; Laboratories; Ligand Binding; Liposomes; Mechanics; Microglia; Military Personnel; Mus; Natural Immunity; Nature; Neurons; Outcome; Pathologic; Pathology; Phagocytosis; Pharmacology; Phase II Clinical Trials; Phenotype; Play; Population; Population Heterogeneity; Production; Publishing; Recovery of Function; Reporting; Role; Soldier; Spinal Cord; Spinal cord injury; Suppressor-Effector T-Lymphocytes; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Time; Traumatic Brain Injury; Veterans; Wild Type Mouse; Work; Wound Healing; behavioral outcome; clinically significant; cognitive function; cytokine; design; functional outcomes; human disease; humanized mouse; improved; improved outcome; innovation; macrophage; monocyte; mouse model; neuroinflammation; new therapeutic target; phase II trial; pre-clinical; public health relevance; response; single-cell RNA sequencing; small molecule; success; targeted treatment; transcriptome; wound

 DESCRIPTION (provided by applicant): Neuroinflammation following TBI exacerbates neuronal and glial death and dysfunction. The monocyte- derived macrophage response is harmful in TBI. However, macrophages are a broadly heterogeneous population and polarized subsets can be critical for wound repair. Our goal is to identify harmful and beneficial components of the innate immune response to TBI and to define when they arise, to identify optimal targets and timing for therapeutic intervention. The ultimate goal is to block harmful responses and enhance reparative ones to improve long-term functional outcomes of TBI. Our recently published study showed that Ccr2-/- mice had reduced monocyte-derived brain macrophages and improved outcomes post-TBI. We hypothesize that pharmacological blockade of human CCR2 will improve TBI. Our new data shows that a CCR2 antagonist, CCX872 (in Phase II clinical trials for nephropathy), given 5 min after TBI in mice expressing human CCR2 blocked 83±2% of the macrophage infiltrate. Aim 1. Determine the therapeutic benefit of the human CCR2 antagonist, CCX872, given after TBI, to mice expressing human CCR2 to inhibit macrophage infiltration into the brain, and to improve pathologic and behavioral outcomes. 1a. Determine the effective dose range and time window of hCCR2 antagonist, CCX872, administered after TBI to block macrophage infiltration to the brain. 1b. Determine the effective dose range and time window of hCCR2 antagonist, CCX872, administered after TBI to improve behavioral functions and histopathology. Our previous published work and our new preliminary single-cell RNA sequencing studies indicate that TBI macrophages are diverse and are not limited to the M1/M2 paradigm. We hypothesize that multiple monocyte- derived macrophages and microglia subsets develop after TBI. Aim 2. Define the diversity of monocyte-derived macrophages and resident microglia in the brain post- TBI by the use of single-cell, whole-transcriptome analysis. 2a. Define the monocyte-derived brain macrophage subsets post-TBI by performing single-cell RNA seq. 2b. Define microglia subsets post-TBI by performing single-cell RNA seq. In the absence of CCR2, a macrophages subset still infiltrates the injured brain after TBI, and is associated with improved outcomes. We hypothesize that CCR2-independent macrophages are protective in TBI. Aim 3. Determine the expression profile, functional role, and requirement for CCR2-independent macrophages in post-TBI outcomes. 3a. Define CCR2-independent macrophage subsets in the brain after TBI by single-cell RNA seq. 3b. Define the functional nature of the CCR2-independent macrophage response to TBI by examining phagocytosis, cytokine production, and T cell suppressor function by these cells. 3c. Determine if CCR2-independent macrophages are beneficial or harmful by depleting them with clodronate liposomes in Ccr2-/- mice after TBI and determining the effects on TBI outcomes. This work will provide the preclinical basis and design for targeting CCR2 in TBI therapy. Furthermore, the work will provide an unprecedented view of macrophage biology in the specific context of TBI. These studies will lead to informed approaches for altering neuroinflammation to improve outcomes for veterans.

 描述（由申请人提供）： TBI后的神经炎症加剧了神经元和神经胶质细胞的死亡和功能障碍。单核细胞衍生的巨噬细胞反应在TBI中是有害的。然而，巨噬细胞是广泛异质的群体，并且极化的亚群对于伤口修复可能是至关重要的。我们的目标是确定对TBI的先天免疫反应的有害和有益成分，并确定它们何时出现，以确定治疗干预的最佳靶点和时机。的 最终目的是阻断有害反应，增强修复性反应，以改善TBI的长期功能结局。 我们最近发表的研究表明，Ccr 2-/-小鼠减少了单核细胞衍生的脑巨噬细胞，并改善了TBI后的结果。我们假设，药理学阻断人CCR 2将改善TBI。我们的新数据显示，在表达人CCR 2的小鼠中，TBI后5分钟给予CCR 2拮抗剂CCX 872（用于肾病的II期临床试验），可阻断83±2%的巨噬细胞浸润。目标1.确定TBI后给予人CCR 2拮抗剂CCX 872对表达人CCR 2的小鼠的治疗益处，以抑制巨噬细胞浸润到脑中，并改善病理和行为结果。 1a.确定在TBI后施用hCCR 2拮抗剂CCX 872以阻断巨噬细胞向脑浸润的有效剂量范围和时间窗。 1b.确定hCCR 2拮抗剂CCX 872在TBI后改善行为功能和组织病理学的有效剂量范围和时间窗。 我们以前发表的工作和我们新的初步单细胞RNA测序研究表明，TBI巨噬细胞是多样化的，并不限于M1/M2范式。我们假设创伤性脑损伤后出现了多个单核细胞衍生的巨噬细胞和小胶质细胞亚群.目标2.通过使用单细胞、全转录组分析来定义TBI后脑中单核细胞衍生的巨噬细胞和常驻小胶质细胞的多样性。 2a.通过进行单细胞RNA测序来定义TBI后单核细胞衍生的脑巨噬细胞亚群。 2b.通过进行单细胞RNA测序来定义TBI后的小胶质细胞亚群。 在缺乏CCR 2的情况下，巨噬细胞亚群在TBI后仍然浸润受伤的大脑，并且与改善的结果相关。我们假设CCR 2非依赖性巨噬细胞在TBI中具有保护作用。目标3.确定TBI后结局中CCR 2非依赖性巨噬细胞的表达谱、功能作用和需求。 3a.通过单细胞RNA测序定义TBI后脑中不依赖CCR 2的巨噬细胞亚群。 3b.通过检查这些细胞的吞噬作用、细胞因子产生和T细胞抑制功能来定义CCR 2非依赖性巨噬细胞对TBI的反应的功能性质。 3c.通过在TBI后Ccr 2-/-小鼠中用氯膦酸盐脂质体消耗CCR 2非依赖性巨噬细胞并确定对TBI结果的影响来确定CCR 2非依赖性巨噬细胞是有益还是有害的。 这项工作将为TBI治疗中靶向CCR 2提供临床前基础和设计。此外，这项工作将在TBI的特定背景下提供前所未有的巨噬细胞生物学观点。这些研究将带来改变神经炎症的明智方法，以改善退伍军人的治疗结果。