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

我的退伍军人管理局相关研究集中在研究创伤性脊髓损伤(SCI)，这是最致残的 影响受伤美军成员的情况。尽管脊髓损伤的存活率仍然很高，但 受伤的破坏性导致实质性残疾，这必须由受伤的退伍军人承担，他们的 家庭和退伍军人医疗保健系统。不幸的是，目前还没有有效的治疗方法。 急性和慢性脊髓损伤患者。因此，开发新的治疗策略势在必行。 对于患有脊髓损伤的退伍军人来说，毁灭性的本质和改善的生活质量。我的研究目标是研究 创伤性脊髓损伤的分子机制和促进再生的新修复策略 促进实验性脊髓损伤模型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移植到人类，包括我们的退伍军人。要达到这些目标 目标，我在3个主要领域进行退伍军人管理局的相关研究。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的假设，即促进生长 途径，由移植的雪旺细胞(SCs)组成，这是一种外周支持细胞，过度表达a 营养因子又称胶质细胞源性神经营养因子(GDNF)，会促进降压的生长 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)形成靶向性连接 称为神经营养因子-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治疗都要好。这项提案的完成将使我们能够揭示 重建脊髓下行通路神经回路的基本机制和识别 脊髓损伤后功能恢复的新治疗策略。第二个研究领域(由退伍军人事务部I01支持 BX003705-01A1)，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途径在脊髓损伤后细胞死亡、组织损伤和功能丧失中起重要作用。 具体地说，我们将确定一种新的线粒体靶向抗氧化化合物XJB的治疗效果 以及成年大鼠临床相关挫伤脊髓损伤后功能恢复的分子机制。 在第三个研究领域(VA绵羊1IS1 BX004405-01)，我已经获得了购买资金 供9名退伍军人管理局资助的研究人员使用的超微II光片荧光显微镜(LSFM) 不同的研究学科，包括神经、肌肉和神经肌肉骨骼(NMS)内的骨生物学 印第安纳波利斯鲁德布什VAMC的研究项目。LSFM是一种创新的设备，它克服了 当前使用的常规方法的许多局限性，并将以高质量、高效率、 精确度和工作效率。获得此LSFM的总体目标是在 资助退伍军人管理局调查人员，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.