TBI is a prevalent and devastating health issue worldwide. Despite extensive research in neuroprotective therapies, and success in pre-clinical models, multiple clinical trials have failed to demonstrate efficacy, such that there are still no targeted treatments available for TBI. TBI is a heterogenous disease, influenced by mechanical forces, genetic factors, and secondary insults that compound the primary injury. A major limitation hindering the development of TBI therapies is the lack of reliable biomarkers of specific injury mechanisms in TBI. Substantial data point to traumatic microvascular injury (TMI) as a key component of TBI-associated disability: pathological studies demonstrate that TMI is a nearly universal, albeit under-studied, endophenotype of TBI and vascular dysfunction underlies many of the chronic neurological symptoms that complicate TBI recovery. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TMI is an attractive target for therapeutic intervention after TBI. The central hypothesis of this proposal is that traumatic microvascular injury is a prominent TBI endophenotype that is predictive of patient outcome. The objectives of the proposed study are to: (1) describe the natural history of TMI using neuroimaging, (2) develop diagnostic and prognostic miRNA biomarkers of TMI, and (3) describe the correlation between the neuroimaging and miRNA biomarkers and clinical outcomes after traumatic brain injury. In the context of this study, the candidate will train in clinical and translational research methods with focused, individualized mentoring to support her transition to independently funded, patient-oriented research. This proposal will leverage an ongoing prospective cohort study of individuals with traumatic brain injury who undergo detailed demographic, clinical, neuroimaging, and neuropsychological assessments from their acute injury through chronic recovery. In addition to completing the proposed research, the applicant will engage in a rigorous training program of didactic courses and mentoring by experts in neurotrauma, brain imaging, miRNAs, and vascular biology. She will gain expertise in clinical study design and management, sequencing and molecular laboratory techniques, and advanced statistical methodologies relevant to clinical research. The applicant's progress and attainment of specific benchmarks in research and career development will be regularly reviewed by her mentors who have extensive experience in training junior investigators and facilitating their transition to independent research careers. Completion of the proposed study will be facilitated by an institutional environment that prioritizes collaboration, and provides exemplary research and career support. Through the conduct of the proposed study, the applicant will make significant contributions to the understanding of traumatic microvascular injury and describe neuroimaging and molecular biomarkers necessary for future projects examining vascular-directed therapies in traumatic brain injury.
Traumatic brain injury (TBI) is a prevalent, worldwide disease for which there are no targeted, effective treatments. Clinical trials in TBI have been limited by the lack of available biomarkers to (1) properly classify this heterogeneous disease, (2) track clinical recovery, and (3) distinguish disease-specific mechanisms, which may vary among patients. The objective of this proposal is to describe the natural history of traumatic microvascular injury (TMI), a prevalent but understudied endophenotype of TBI, using neuroimaging and miRNA biomarkers to facilitate rationally-designed, mechanistic clinical trials of vascular-directed therapies for TBI.
| Haber, Margalit; Amyot, Franck; Kenney, Kimbra et al. (2018) Vascular Abnormalities within Normal Appearing Tissue in Chronic Traumatic Brain Injury. J Neurotrauma 35:2250-2258 |
