New bioinformatic and statistical methods will be developed to study traumatic central nervous system including spinal cord, which provokes an inflammatory response that generates substantial secondary tissue damage and inhibits neuronal regeneration. Anti-inflammatory treatment of human spinal core injury and its timing must be based on knowledge of the types of cells participating in the inflammatory response, the time after injury when they appear and the nature of their actions. However, inflammatory cascades and relationship with neurogenesis are complicated and consequence of central nervous system injury including spinal cord injury is poorly understood. Invading macrophages and resident microglia cells, the two major cell types that are from monocytic lineage play major role in the inflammatory process. Due to the lack of specific markers, the functional roles of invading macrophages from activated microglia within injured spinal cord are not largely unknown. We propose to use microarray techniques to investigate expression profiles on microglia and macrophages in different time points and the expression network between inflammation and neurogenesis. New methods are proposed to label defined cell populations in microglia/macrophage deleted mice. New statistical techniques will be developed to address directly the challenges from our biological studies. These include removing intensity effect of the Affymetrix data, identifying significant genes and determining gene expressions patterns over time, identifying a small group of genes that differentiate invading macrophages from activated microglia in the spinal cord, among others. They involve the statistical estimation, testing, variable selection, classification and network modeling in high-dimensional feature spaces. These emerging problems will be confronted via developing new statistical methods to address the challenges associated with high-dimensionality. At the same time, the investigators also intend to provide fundamental understanding, via asymptotic analysis and simulation studies, to these problems and their associated methodologies. A distinguished feature of the proposal is the combination the strengths of our expertise in statistics and molecular biology to gain better understanding of molecular disturbances in spinal cord and central nervous system injury.
The proposal investigates molecular disturbances in spinal cord and central nervous system injury. Our aims include identifying genes that reveal the distinct functional profiles of resident microglia and invading macrophages in spinal cord injury, and selecting the genes that are uniquely altered during specific facets of the neuronal response to inflammation. These approaches can not only help us understand the molecular mechanisms of inflammatory responses in spinal cord injury, but also potentially identify genes to be targeted for therapeutic intervention following spinal core injury. In addition, our developed cutting-edging statistical techniques and bioinformatic tools can be applied to other biological and statistical researches. The project will also integrate research and education by working closely with students and funding them in the form of research assistantships, creating datasets, and developing publicly available computer code (both made available through the web) for each of the main research endeavors funded by this proposal. Various research findings and examples will be simplified and taught in both undergraduate and graduate courses. In particular, they will be used in supervising undergraduate senior theses and Ph.D. theses. Postdoctoral fellows and underrepresented groups will be trained as a part of our research investigation. The results will be disseminated broadly through presentations at seminars, conferences, professional association meetings, and internet.
