BLR&D Research Career Scientist Award Application for Xiao-Ming Xu, PhD

BLR

• 批准号: 9911971
• 负责人: XIAO-MING XU
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911971
• 关键词: Acute; Adult; Affect; Anatomy; Animal Model; Antioxidants; Area; Award; Behavioral; Biology; Cardiolipins; Cell Death; Cellular biology; Cerebral cortex; Chronic; Clinical; Collaborations; Devices; Discipline; Distal; Doctor of Medicine; Doctor of Philosophy; Educational process of instructing; Electrophysiology (science); Experimental Models; Family; Funding; Goals; Grant; Growth; Health; Healthcare Systems; Histologic; Human; Image; Imaging technology; Indiana; Injury; Journals; K-Series Research Career Programs; Lead; Light; Lipids; Mediating; Medical center; Mentors; Mentorship; Military Personnel; Mission; Mitochondria; Modeling; Molecular; Molecular and Cellular Biology; Motor Neurons; Muscle; Natural regeneration; Nature; Nerve Fibers; Nerve Regeneration; Neurology; Neuronal Plasticity; Neurosciences; Neurotrophin 3; Paper; Pathway interactions; Patients; Peer Review; Peripheral; Play; Postdoctoral Fellow; Productivity; Publications; Publishing; Quality of life; Rattus; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Role; School Dentistry; Schwann Cells; Science; Scientist; Secure; Services; Sheep; Signal Pathway; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Spinal nerve structure; Students; Supporting Cell; Survival Rate; Testing; Tissues; Training; Translating; Trauma; United States National Institutes of Health; Universities; Veterans; Visit; Walkers; bone; career; clinically relevant; combinatorial; cytochrome c; disability; doctoral student; effective therapy; experience; fluorescence microscope; functional loss; glial cell-line derived neurotrophic factor; imaging facilities; improved; in vivo imaging; indexing; injured; innovation; interdisciplinary approach; member; mid-career faculty; neural circuit; neuromusculoskeletal; neuroprotection; neurotrophic factor; novel; novel therapeutic intervention; novel therapeutics; optogenetics; overexpression; post-doctoral training; pre-clinical; professor; programs; recruit; relating to nervous system; repaired; tenure track; treatment effect; treatment strategy

My VA-related research focuses on studying traumatic spinal cord injury (SCI), which is among the most disabling conditions affecting wounded members of the U.S. military. Although survival rates for SCI remain high, the devastating nature of the injury results in substantial disability, which must be borne by the injured veterans, their families, and the VA health-care system. Unfortunately, there has been no effective treatment available for patients with acute and chronic SCIs. Therefore, developing novel treatment strategies is imperative to mitigate the devastating nature and improve quality of life for our veterans with SCI. The goal of my research is to study molecular mechanisms underlying traumatic SCI and develop novel repair strategies to promote regeneration of the injured spinal cord and enhance functional recovery in experimental models of SCI. My long-term goal is to translate effective treatment strategies from animal models to humans, including our veterans. To reach these goals, I conduct VA-related research in 3 major areas. In the first research area (supported by VA I01 BX002356-01 and I01 BX002356-04), my lab is testing an innovative hypothesis that a growth-promoting pathway, composed of grafted Schwann cells (SCs, a type of peripheral supporting cells) overexpressing a trophic factor called glial cell line-derived neurotrophic factor (GDNF), will promote the growth of descending spinal nerve fibers across an injury gap to project to the distal host spinal cord. These regenerated nerve fibers will form target-specific connections with lumbar motoneurons (MNs) overexpressing another neurotrophic factor called neurotrophin-3 (NT-3). We also hypothesize that such a combinatorial approach will lead to greater functional recovery than any single treatment alone. Completion of this proposal will allow us to reveal mechanisms fundamental to rebuilding neural circuitry of the descending spinal cord pathways and to identify new therapeutic strategies for functional recovery after SCI. In the second research area (supported by VA I01 BX003705-01A1), we propose to investigate whether a novel lipid signaling pathway, namely the cardiolipin (CL)- cytochrome c pathway, plays a role in mediating cell death, tissue damage, and functional loss after SCI. Specifically, we will determine the treatment effect of a new mitochondrial targeted antioxidant compound XJB and its molecular mechanism underlying functional recovery after a clinically-relevant contusive SCI in adult rats. In the third research area (supported by VA ShEEP 1IS1 BX004405-01), I have secured funding to purchase an UltraMicroscope II Light Sheet Fluorescence Microscope (LSFM) for use by 9 VA-funded investigators with different research disciplines including neural, muscle, and bone biology within the NeuroMusculoSkeletal (NMS) Research Program at the Roudebush VAMC in Indianapolis. The LSFM is an innovative device that overcomes many limitations of currently used conventional approaches and will advance science with high quality, efficiency, precision, and productivity. The overall objective of obtaining this LSFM is to create new collaborations among funded VA investigators that lead to innovative solutions for health problems facing our veterans.

我的 VA 相关研究重点是研究创伤性脊髓损伤 (SCI)，这是最致残的疾病之一 影响美国军人受伤人员的情况。尽管 SCI 的存活率仍然很高， 伤害的破坏性会导致严重残疾，这必须由受伤的退伍军人及其家属承担 家庭和 VA 医疗保健系统。不幸的是，目前还没有有效的治疗方法 急性和慢性 SCI 患者。因此，开发新的治疗策略势在必行 毁灭性的性质并改善我们患有 SCI 的退伍军人的生活质量。我的研究目标是研究 创伤性 SCI 的分子机制并开发新的修复策略以促进再生 损伤脊髓并增强 SCI 实验模型的功能恢复。我的长期目标是 将有效的治疗策略从动物模型转化为人类，包括我们的退伍军人。为了达到这些 目标，我在 3 个主要领域进行 VA 相关研究。在第一个研究领域（由VA I01支持） BX002356-01 和 I01 BX002356-04），我的实验室正在测试一个创新假设，即促生长 途径，由移植的雪旺细胞（SC，一种外周支持细胞）组成，过度表达 营养因子称为胶质细胞源性神经营养因子（GDNF），会促进下行神经细胞的生长 脊神经纤维穿过损伤间隙投射到远端宿主脊髓。这些再生的神经纤维 将与过度表达另一种神经营养因子的腰椎运动神经元（MN）形成目标特异性连接 称为神经营养素-3 (NT-3)。我们还假设这种组合方法将带来更大的效果 功能恢复优于任何单一治疗。完成该提案将使我们能够揭示 重建脊髓下行通路的神经回路并识别的基本机制 SCI 后功能恢复的新治疗策略。第二个研究领域（VA I01支持） BX003705-01A1），我们建议研究是否有一种新的脂质信号通路，即心磷脂（CL）- 细胞色素 c 通路在介导 SCI 后的细胞死亡、组织损伤和功能丧失中发挥作用。 具体来说，我们将确定一种新型线粒体靶向抗氧化化合物XJB的治疗效果 及其成年大鼠临床相关挫伤性 SCI 后功能恢复的分子机制。 在第三个研究领域（由 VA ShEEP 1IS1 BX004405-01 支持），我已获得资金购买 UltraMicroscope II 光片荧光显微镜 (LSFM)，供 9 名 VA 资助的研究人员使用 NeuroMusculoSkeletal (NMS) 内的不同研究学科，包括神经、肌肉和骨骼生物学 印第安纳波利斯 Roudebush VAMC 的研究项目。 LSFM 是一种创新设备，克服了 当前使用的传统方法存在许多局限性，并将以高质量、高效率、 精度和生产率。获得此 LSFM 的总体目标是在 资助退伍军人事务部研究人员，为退伍军人面临的健康问题提供创新的解决方案。