Immune function within the central nervous system (CNS) plays an important role regulating the health of the cellular constituents, and CNS immune dysfunction is implicated in many neurodegenerative and inflammatory diseases, such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's. However, given their importance, the origin, recruitment, and effector mechanisms of those cells that regulate overall CNS immune function remain enigmatic. This project will investigate the contribution and function of bone marrow-derived progenitor cells to the CNS population of microglia, the resident immune cells. Following establishment of hematopoietic chimerism via transplantation of bone marrow cells from green fluorescent protein transgenic mice into wild type mice, we will identify hematopoietically-derived cells that have newly arrived within the CNS. Utilizing quantitative flow cytometry and qualitative histology/microscopy techniques, we will investigate the cellular and molecular phenotype of these new CNS-infiltrating cells compared to resident microglia and determine the contribution rate of the hematopoietic compartment. Furthermore, this experimental model will allow for the isolation of donor hematopoietically-derived and resident microglia, thus allowing for mechanistic studies of both the immune function and neurotransmitter influence. The major hypothesis of the project states that in normal, non-disease-affected mice, there will be a small, but consistent, contribution to the CNS of cells that originate from the hematopoietic system, and that these newly engrafted precursors will demonstrate enhanced immune cell markers and physiologic function whereas resident microglia will exhibit a neural phenotype and respond to neurotransmitters more robustly. We hypothesize that hematopoietically-derived cells will transition from an immune to a neural responsive phenotype over time. The detailed molecular, cellular, and anatomical characterization and functional investigations proposed in these studies will provide a strong foundation for future studies. For example, perturbations of the neuro-immune system in various CNS diseases will allow for further advancement of our understanding into the onset and progression of CNS disorders. Finally, the research outlined in this proposal serves as an ideal mechanism for the active engagement of undergraduate students. The clinical relevance provides a strong, tangible starting point for our students, and they gain experience in how basic research contributes to the understanding of CNS diseases and disorders. Furthermore, the interdisciplinary nature and multifaceted approach of this project allows them to actively participate, and importantly, help steer the direction of the project themselves, in the manner in which many current research institutions are tackling biological questions.
The interplay between the central nervous system (CNS) and the immune system lies at the heart of many current neurodegenerative and inflammatory diseases, including multiple sclerosis, Alzheimer's, and Parkinson's. The goal of this research project is to investigate and elucidate the origin and relative function of two important CNS cell populations: resident microglia and hematopoietically-derived precursor cells. Understanding how newly engrafted precursor immune cells function, compared to microglia, could uncover new avenues for treatment of many CNS diseases.
