The research scope of this CAREER program significantly impacts the large societal crisis of traumatic brain injury, particularly since recent studies have shown that even mild brain injuries may result in chronic effects to a patient. The findings identified in the proposed research will have profound impact on elucidating key signaling events that may promote neural regeneration via stem cell recruitment after traumatic brain injury. Upon understanding these basic signals, the investigator will evaluate biomaterial-based paradigms to then modulate endogenous stem cell recruitment and subsequently neural regeneration. A unique educational program will also be developed in parallel to and integrated with the research program, as students ranging from high school to graduate school will actively conduct the proposed research. Additionally, the investigator will develop a guided-inquiry scientific module for high school students aimed at developing scientific analytical skills. Collectively, this CAREER proposal will address fundamental gaps in understanding and modulating neural regeneration after brain injury and provide substantive research skill sets for the next generation of engineers and scientists.
Injury-related chemokines, such as stromal cell derived factor-1a (SDF-1a), have been implicated in stimulating endogenous neural stem/progenitor cells (NSPC) proliferation and ectopic migration toward pericontused tissue after traumatic brain injury. A transient yet critical SDF-1a gradient is thought to play a key role in recruitment of endogenous NSPCs originating from niches located a great distance away from the site of injury (i.e., subventricular zone). However, the mechanism for the temporal and spatial propagation of SDF-1a from the pericontused tissue to NSPC niches is largely unknown. It is postulated that one of two potential mechanisms may be occurring: A) simple diffusion of SDF-1a from cells residing within the pericontused tissue, and/or B) autocrine/paracrine mediated propagation of SDF-1a gradient. Understanding the mechanisms by which such critical chemotactic gradients are established, particularly in the injured brain, will better inform drug delivery strategies aimed at amplifying endogenous NSPC recruitment for neural regeneration. The long-term research goal of this CAREER program is to develop regenerative therapies that harness inherent endogenous repair mechanisms for traumatic brain injury, leading to improved functional outcomes in cognitive and motor functions. The proposed research is the first step in achieving this long-term goal whereby the primary research objective is three-fold: i) elucidate mechanisms of injury-related chemotactic gradients formation, ii) develop drug delivery strategies that exploit endogenous chemotactic signaling, and iii) determine the impact of injury-related chemotactic gradients on recruitment and neuronal integration of endogenous NSPCs. The proposed research directly addresses current gaps in the knowledge by employing a unique combination of mathematical modeling and simulation, in vivo animal models, and whole tissue 3-D confocal microscopy analysis to first predict, then test/validate proposed diffusion models for SDF-1a gradient formation. Establishing a valid and reliable model of SDF-1a signaling will enable modeling/simulation of drug delivery approaches to modulate SDF-1a signaling to prolong the presence of the gradient (i.e., sustained controlled release vs. bolus injection). Concurrently, the impact of SDF-1a gradients on the recruitment and integration of endogenous NSPCs will be evaluated via both immunohistological and electrophysiological techniques. Collectively, the integration of modeling/simulation and experimental methodologies demonstrates the intellectual merit contributions of the proposed studies to the traumatic brain injury, drug delivery, and regenerative medicine communities.
