Our brain and immune system interface throughout the body to communicate in health and disease, but whether neurological disease results as a failure of neuro-immune cross-talk is currently unknown. Our immune system is in constant flux- highly in tune with our thoughts, feelings, and behavior. It isn't surprising that an injury as devastating as a traumatic brain injury (TBI) has long-term consequences on our thoughts, feelings, and behavior. And so, it stands to reason that the immune system itself is also compromised after TBI. Indeed, experimental and clinical studies alike show widespread changes in circulating leukocytes and plasma cytokine levels of acute TBI patients. While these measures serve as useful correlates of functional outcome, the source of these changes is often overlooked. Bone marrow (BM) hematopoietic stem cells (HSCs) continuously give rise to all blood cell types that make up the immune system, potentially making them key cellular effectors of neuro-immune communication. Consequently, changes in the health of the bone marrow niche alter the composition of our immune system and have a profound impact on immunity. The self- renewing capacity of HSCs and their location in the body make them viable targets for therapeutic manipulation.
The aim of this proposal is to understand how TBI affects BM hematopoietic function, and in turn, how downstream changes in peripheral immunity impact the progression of TBI. By tracking the outcome of chronically injured mice over time and assessing their response to infection we will ascertain the extent to which TBI causes BM dysfunction, premature senescence, and bidirectional impairment. We will implement a novel BM chimera strategy to study the neurological consequences of TBI- induced changes in BM function and whether these changes can be self-corrected (Aim 1). Using this comprehensive description of the neuro-immune processes underlying chronic TBI we will then determine the molecular mechanisms by which BM HSCs go awry with brain injury (Aim 2) and intervene therapeutically at late time points to eliminate senescent microglia/macrophages, restore innate immunity, and ameliorate chronic inflammation (Aim 3). The completion of these aims seeks to unmask the role of BM as a major communication hub of the neuro-immune axis, and its progenitor cells as the primary effectors of chronic inflammation, immune dysfunction, and TBI disease progression. To further guide my research and career development, I will be advised by an interdisciplinary team of experienced mentors and experts in traumatic brain injury, innate immunity, and stem cell biology. This ensemble of mentors will ensure my research project and career development needs are met through frequent meetings and interaction. My overall career goal is to be an independent investigator at a major research institution. The K award would provide the springboard required to reach this goal, allow me to develop my own original research program, and put me on a path to be an independent, early stage investigator.
Traumatic brain injury (TBI) causes long-lasting effects on the brain and body characterized by progressive neurodegeneration and chronic inflammation, respectively. The proposed studies will investigate the bidirectional impact of TBI on bone marrow and aim to reveal how changes in the immune system accelerate aging and brain injury. The determination of hematopoietic stem/progenitor cells and bone marrow-derived leukocytes as causal factors of neurological impairment will dramatically improve our understanding of the neuro-immune axis, provide means for improving diagnostics, and open up new windows of treatment for TBI survivors.
