Multipronged approach to diminish sympathetic hyperreflexia and ensuing cardiovascular and immune dysfunction after spinal cord injury

多管齐下减少脊髓损伤后交感神经反射亢进和随之而来的心血管和免疫功能障碍

• 批准号: 10598487
• 负责人: Veronica Jean Tom
• 金额: $ 42.85万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598487
• 关键词: Affect; American; Animals; Autonomic Dysfunction; Autonomic Dysreflexia; Axon; Bacterial Pneumonia; Bladder; Blood; Brain Stem; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chest; Chronic; Collaborations; Contusions; Disparate; Event; Fiber; Functional disorder; Hyperreflexia; Hypertension; Immune System Diseases; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunosuppression; Individual; Infection; Injury; Interruption; Life; Mediating; Modeling; Morbidity - disease rate; Neurons; Organ; Output; Peptides; Persons; Physiological; Play; Predisposition; Prophylactic treatment; Public Health; Recovery of Function; Regulation; Rodent; Role; Secondary to; Serotonin; Severities; Signal Transduction; Silver; Spinal; Spinal Cord; Spinal cord injury; Spleen; Sympathetic Nervous System; System; TNF gene; Testing; Therapeutic; Tissues; Transplantation; Vertebral column; antagonist; cardiovascular infection; clinically relevant; cytokine; efficacy evaluation; experimental study; hemodynamics; immune function; improved; injured; mind control; mortality; nerve supply; prevent; receptor; response; tumor necrosis factor-alpha inhibitor

PROJECT SUMMARY Spinal cord injury (SCI) is a devastating event sustained by as many as 1.3 million Americans. While not often appreciated, cardiovascular disease and susceptibility to infection are leading causes of mortality and morbidity in individuals living with SCI. One major reason thought to underlie these issues is SCI-induced dysregulation of the sympathetic nervous system. In this proposal, we will use a clinically-relevant contusion rodent SCI model to test the hypothesis that intracellular sigma peptide (ISP) will promote sufficient sprouting of serotonergic axons onto neurons in the spinal sympathetic circuit below the SCI to normalize sympathetic activity after injury. Furthermore, we hypothesize that administering a combining ISP and inhibition of soluble tumor necrosis factor alpha (sTNFα) with XPro1595 – which target different root causes of sympathetic hyperreflexia after SCI (i.e., interrupted supraspinal input the spinal sympathetic circuit and sTNFα-induced maladaptive plasticity of the spinal sympathetic circuit, respectively) – will have synergistic effects on improving cardiovascular and immune function after SCI.

项目摘要 脊髓损伤（SCI）是一种毁灭性的事件，多达130万美国人。虽然不经常 心血管疾病和感染易感性是死亡和发病的主要原因 在SCI患者中。一个主要的原因被认为是这些问题的基础是SCI诱导的失调 交感神经系统。在这个建议中，我们将使用临床相关的挫伤啮齿动物SCI模型 为了检验胞内σ肽（ISP）将促进肾上腺素能受体的充分发芽的假设， 将轴突连接到SCI下方的脊髓交感神经回路中的神经元上，以使损伤后的交感神经活动正常化。 此外，我们假设，联合使用ISP和抑制可溶性肿瘤坏死因子， α（sTNFα）与XPro 1595-其靶向SCI后交感神经反射亢进的不同根本原因（即， 脊髓交感神经回路和sTNFα诱导的脊髓背角适应不良可塑性 脊髓交感神经回路）-将有协同作用，改善心血管和免疫 SCI后的功能