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

我的VA相关研究主要集中在研究创伤性脊髓损伤（SCI），这是最致残的 影响美军受伤人员的情况。尽管SCI的存活率仍然很高， 伤害的破坏性导致严重残疾，必须由受伤的退伍军人承担， 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，开发新的治疗策略是当务之急，以减轻 的破坏性和改善生活质量为我们的退伍军人与脊髓损伤。我研究的目的是研究 创伤性脊髓损伤的分子机制，并开发新的修复策略，以促进再生， 对脊髓损伤的保护作用，促进脊髓损伤后功能恢复。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。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 I 01支持 BX 002356 -01和I 01 BX 002356 -04），我的实验室正在测试一个创新的假设， 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 胶质细胞源性神经营养因子（GDNF）是一种能促进神经生长的营养因子， 脊髓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）形成靶向特异性连接 称为神经营养素-3（NT-3）。我们还假设，这种组合方法将导致更大的 功能恢复比任何单一的治疗。完成这项提案将使我们能够揭示 重建下行脊髓通路神经回路的基本机制， SCI后功能恢复的新治疗策略。在第二个研究领域（由VA I 01支持 BX 003705 - 01 A1），我们建议研究一种新的脂质信号通路，即心磷脂（CL）- 细胞色素c途径在介导SCI后的细胞死亡、组织损伤和功能丧失中起作用。 具体来说，我们将确定一种新的线粒体靶向抗氧化剂化合物XJB的治疗效果。 以及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 1 IS 1 BX 004405 -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， 不同的研究学科，包括神经肌肉骨骼系统（NMS）内的神经，肌肉和骨骼生物学 在印第安纳波利斯的Roudebush VAMC的研究计划。LSFM是一种创新设备， 目前使用的传统方法的许多局限性，并将以高质量，高效率， 精度和生产力。获得这一LSFM的总体目标是在以下方面建立新的合作： 资助退伍军人事务部的调查人员，为退伍军人面临的健康问题提供创新的解决方案。

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.