Program to Characterize Evolving Endophenotypes of Degeneration After Traumatic Brain Injury (PROCEED-TBI)
Abstract
Although many therapies for traumatic brain injury (TBI) have been shown to improve outcomes in rodent models of TBI, none have proven effective in human TBI drug trials, forcing re-evaluation of TBI study design. A major research gap for these previous trials includes enrollment of individuals based on the severity of their TBI symptoms rather than their specific forms of brain damage. In retrospect, it seems unrealistic to expect that one drug can address multiple forms of brain injury that differ from patient to patient. Another major design flaw has been the expectation that rodent TBI models replicate the spectrum of pathologies encountered in human TBI. Therefore, we have established a PROgram to Characterize Evolving Endophenotypes of Degeneration after Traumatic Brain Injury (PROCEED-TBI). The scientific terms, endophenotypes and evolving embody how different types of brain damage/ pathologies change over time in individual patients. This program brings together a unique multidisciplinary team who collectively have made important contributions over three decades to the TBI field, spanning experimental identification of mechanisms that trigger progressive damage (degeneration) after TBI in animal models to better understand different forms of brain damage in human TBI. For this Program, we seek to build the knowledge and tools necessary to bridge the gap between animal TBI therapeutic research and the design of human TBI drug trials. PROCEED-TBI will address these challenges according to key FY21 TBIPHRP Focus Area 1, Understand - by addressing gaps in foundational science and etiology of TBI, specifically, 1a, understanding long-term outcomes and understanding the role of endophenotypes and pathophysiology on TBI, and Focus Area 2: Prevent and Assess: (2a) Identification and validation of biomarkers or other objective markers for diagnosis, prognosis, or monitoring of TBI, and 2b) Validation of objective tools/ methods for assessing and real-time health status monitoring of TBI. For this Program, we will leverage our unique access to large archives of human TBI post-mortem brains, as well as MRI scans and blood samples from living humans with TBI, to develop advanced biomarker tests that can guide future clinical trials and eventually clinical practice. The human materials will be evaluated in parallel with identical examinations of TBI in swine models, which are considered to best replicate the injury mechanisms and pathologies of human TBI. Notably, the swine TBI models permit direct comparisons of the brain imaging and blood biomarker findings with evolving brain pathologies in the same animals. Therefore, the findings in the swine models can be extrapolated to enhance interpretation of human TBI data and validate the biomarker techniques. Over four Projects, we propose to evaluate pathological changes over 6 months after TBI in humans and swine. Although changes over this timespan are not currently well understood, they are nonetheless important for determining which forms of pathologies continue to progress and/or significantly contribute to outcome. Validation of biomarkers to follow these changes will be essential to evaluate the effectiveness of therapies in future clinical trials. Project 1 will determine the major forms of brain pathology, such as loss (degeneration) of nerve fibers that span the white matter and persisting damage to brain blood vessels. Project 2 will evaluate the sensitivity of advanced brain imaging (MRI) techniques to identify these evolving brain pathologies. Project 3 will identify the most sensitive blood biomarkers that indicate the presence of specific brain pathologies. Project 4 will determine the extent of endophenotype burden, which will be correlated to clinical outcomes. Overall, this Program will identify important pathologies of TBI that could serve as therapeutic targets. At the same time, this Program will develop new advanced brain im
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311039
Entities
People
- Douglas Smith
Organizations
- United States Army
- University of Pennsylvania