Hematopoietic dysfunction and immune suppression after spinal cord injury

脊髓损伤后的造血功能障碍和免疫抑制

• 批准号: 9527648
• 负责人: Randall S. Carpenter
• 金额: $ 3.89万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527648
• 关键词: Acute; Affect; Agonist; Anatomy; Animals; Attenuated; Bacterial Infections; Biological Assay; Blood; Bone Marrow; Bone Marrow Transplantation; Cell Proliferation; Cell physiology; Cells; Chest; Chronic; Clinical; Clinical Data; Clinical Research; Complication; Data; Development; Ensure; Erythrocytes; Experimental Models; Flow Cytometry; Functional disorder; Future; Genetic; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hour; Immune; Immune System Diseases; Immune system; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Impairment; Infection; Inflammatory; Injections; Injury; Innate Immune System; Laminectomy; Life; Lipopolysaccharides; Location; Luciferases; Lymphoid Tissue; Mitotic; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Neurologic; Operative Surgical Procedures; Oxygen; Patients; Phenotype; Physiological; Process; Quality of life; Regulation; Reporter; Residual state; Spinal; Spinal Cord transection injury; Spinal cord injury; Spleen; Stimulus; Stress; Sympathetic Nervous System; TNF gene; Testing; Therapeutic; Time; Toll-like receptors; Transgenic Organisms; Trauma; experimental study; immune function; immune system function; improved; in vivo; insight; mortality; mouse model; nerve supply; novel; patient population; precursor cell; response; spatiotemporal; stem; therapy development; tool; trafficking

Project Summary (Abstract) Clinical and experimental data indicate that immune system function is impaired after SCI; however, the mechanisms underlying post-injury immune dysfunction are incompletely understood. Given that immune cells are born in generative lymphoid tissues (e.g., bone marrow), it is likely that SCI adversely affects hematopoiesis, i.e., the process of forming functional blood and immune cells from hematopoietic stem and progenitor cells (HSPCs) in bone marrow. There is little data on this topic although two clinical studies support the hypothesis that deficits in hematopoiesis are causal in post-injury immune suppression. The goal of this proposal is to use a mouse model to determine if and how SCI adversely affects hematopoiesis and how this contributes to immune suppression. We hypothesize that high-level SCI will cause hematopoietic dysfunction by altering normal sympathetic activity to the bone marrow hematopoietic niche and that this will contribute to immune suppression. Experiments in Aim 1 will define the spatiotemporal dynamics of hematopoiesis and also evaluate HSPC function at acute and chronic time points after SCI. These data will be the first to define hematopoiesis and/or hematopoietic dysfunction in an experimental model of SCI. Even if SCI reduces numbers or function of HSPCs, some stem/precursor cells will undoubtedly persist in the bone marrow. Experiments in Aim 2 will introduce an inflammatory stimulus to “challenge” these residual cells in the hematopoietic niche and reveal whether post-injury immune suppression is caused by an impaired ability to stimulate HSPC mobilization, survival and differentiation. Together, data from this proposal will provide the first comprehensive analysis of acute and chronic post-SCI changes in hematopoiesis. Such data could provide novel insight needed to develop therapies capable of modulating hematopoiesis and immune function to improve the quality of life for SCI patients.

项目摘要（摘要） 临床和实验数据表明，SCI后免疫系统功能受损;然而， 损伤后免疫功能障碍的潜在机制还不完全清楚。鉴于免疫细胞 在生殖淋巴组织中出生（例如，骨髓），SCI可能会对 造血作用，即，从造血干细胞形成功能性血液和免疫细胞的过程， 骨髓造血祖细胞（HSPCs）。关于这一主题的数据很少，尽管两项临床研究支持 假设造血缺陷是损伤后免疫抑制的原因。这个目标 一个建议是使用小鼠模型来确定SCI是否以及如何对造血产生不利影响，以及这是如何发生的。 有助于免疫抑制。我们假设高水平的脊髓损伤会导致造血功能障碍， 通过改变正常的交感神经活动对骨髓造血生态位的功能障碍， 这将有助于免疫抑制。目标1中的实验将定义时空动态 并评估SCI后急性和慢性时间点的HSPC功能。这些数据将 成为第一个在SCI实验模型中定义造血和/或造血功能障碍的人。即使 SCI减少了HSPCs的数量或功能，一些干细胞/前体细胞无疑会在骨骼中存在 骨髓目标2中的实验将引入炎性刺激以"挑战"这些残余细胞。 造血生态位，并揭示是否损伤后免疫抑制是由受损的能力， 刺激HSPC动员、存活和分化。总的来说，这项提案的数据将提供第一个 急性和慢性SCI后造血变化的综合分析。这些数据可以提供 需要新的见解来开发能够调节造血和免疫功能的疗法， 提高SCI患者的生活质量。