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

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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.