Tuesday, February 4, 2025
2/4/2025
This study will establish the molecular mechanism linking mild repetitive traumatic brain injury (mrTBI) and onset of tau pathology that is associated with Alzheimer’s disease (AD). Our preliminary data suggest that endoplasmic reticulum stress is a notable and long-lasting cascade that is activated by injury. ER stress activates a protein called PERK, which is responsible for initiating protective pathways that help restore ER function. However, long- term activation of PERK leads to cell death. Brain cells are particularly susceptible to PERK-mediated cell death. Indeed, a common sign between TBI and AD is PERK hyperactivity. We recently established that another com- mon pathological hallmark of TBI and AD, abnormal aggregation of the protein tau, is driven by chronic activation of PERK. PERK induces tau to adopt toxic conformations that are associated with disease. Therefore, the overall hypothesis of this project is that TBI induces long-lasting activation of PERK, which in turn catalyzes the formation of pathological tau species. This ultimately leads to increased risk for AD. We will test our hypotheses using mouse models in two aims. In Aim 1, we will determine the conditions under which mrTBI causes activation of PERK. To accomplish this objective, mice will be subjected to mrTBI at different intensities and for different time points, and the levels of active PERK will be measured. In addition, we will determine the extent of tissue that shows PERK activity. In Aim 2, we will manipulate PERK activity in mouse models of tauopathy that have suffered mrTBI. We expect that PERK activation will cause more tau pathology and induce damage to brain function. Conversely, PERK inhibition will restore brain function and prevent tau pathology. Aim 3 will determine the va- lidity of using PERK as a biomarker of TBI. Our preliminary data suggest that individuals who suffered one or more TBIs in their lifetime have two times more active/total PERK ratio in their blood. These data support our enthusiasm to expand our studies into a much larger cohort. If successful, this grant will not only identify a molecular mechanism that links injury and AD, but it will also highlight a key pathological pathway replete with therapeutic targets. Logical extensions of these studies involve testing inhibitors of the PERK pathway for po- tential therapeutic value. It will also offer relief to the 1.7 million people in the United States who suffer a TBI annually. Our expertise in ER stress, PERK, tau, AD, and TBI makes us uniquely suited to accomplish the pro- posed work. In addition, the unique resources available to my lab, such as small animal MR imaging, cohort biospecimens and clinical histories, and the UF Viral Production Core have strengthened the impact of our work and brought us closer to understanding the mechanisms of tau-mediated neurotoxic events stemming from the ER.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).