Project Summary/Abstract Traumatic brain injury (TBI) initiates primary and secondary damage that may lead to a significantly increased risk for the development of neurodegenerative disorders such as frontotemporal lobar dementia (FTLD) and motor neuron diseases like amyotrophic lateral sclerosis (ALS). Currently there are no standard treatments or cures for TBIs or associated neurodegenerative disorders other than symptomatic treatment and supportive therapies. The goal of this project is to assess and catalogue the extent of FTLD- and ALS-like neurodegenerative effects on cortical neurons, hindbrain motor and premotor neurons, and spinal cord motor neurons following a TBI. The overall objective of this project is twofold: first, to provide a thorough analysis of the FTLD- and ALS- like long-term neurodegenerative effects that will help to alleviate a knowledge gap with specific cellular information concerning the neurodegenerative pathologies following a TBI; and secondly, as the basis of a feasibility study for a much broader investigation into treatment therapies designed to minimize the inherent risk of developing TBI-related neurodegenerative disease later in life. The specific aims of this study are designed to determine the neurodegenerative effects of secondary injuries in an animal model of TBI. These effects include the changes in cellular phenotypes and functions as measured through data derived from immunohistochemical (IHC) and RNA-seq analysis. IHC analysis will focus on known and clinically relevant specific markers of FTLD- and ALS-like neurodegeneration including protein translocations and aggregations in the targeted areas (frontal cortex, hindbrain, cervical spinal cord). RNA-seq analysis will be performed on ipsi- and contralateral areas of the frontal cortex and cervical spinal cord. Analysis will be performed to detect differentially expressed genes and alternative spliced transcripts between injured and uninjured hemispheres of a TBI animal model to tissue collected from uninjured control animals. The data and knowledge obtained from these specific aims will be used to design preventative therapies to alleviate the risk of developing future neurodegenerative disease following TBI.

Project Narrative The proposed research is relevant to public health in that it seeks to understand the chronic neurodegenerative effects of secondary injuries caused by traumatic brain injuries and its link to frontotemporal lobar dementia (FTLD) and Amyotrophic lateral sclerosis (ALS) like conditions. This project is relevant to the mission of NIH as it seeks fundamental knowledge to reduce the burden of neurological disease through the design of early intervention therapies.