The Role of Neuroimmune-Neuroendocrine Integration and Premature Hypothalamic Aging in TBI-Related Neurodegeneration
Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity among military and civilian populations. Among the Soldiers who survive conflicts in Iraq/Afghanistan, TBI accounts for 11-23% of their casualties, more than any other war in recent U.S. history. From 2000-2014, for all TBIs diagnosed in U.S. military personnel, 82.4% were classified as mild TBI (mTBI) (involving vehicle crashes, falls, and sports and military training activities), with 50% resulting from multiple head injuries. Similarly, an estimated 80% of civilian TBIs arise from mTBI. It is estimated that more than 5 million Americans are living with disabilities from TBI, which has long been recognized as a risk factor for Alzheimer’s disease and related dementias (ADRD). Mild TBI (particularly repetitive mTBI r-mTBI) is now recognized to be a major health concern, with apparent cumulative effects of injuries on neurological outcomes. To date, clinical trials have focused on moderate to severe TBI, and all have failed. The pathobiology of r-mTBI is, as yet, poorly understood: we do not fully know the timeline or detail of the complex TBI sequelae; the relationship between neuroreparative and neurodegenerative mechanisms is not clear: and the influence of risk or resiliency factors is not known. Clinical studies in human TBI patients are insufficient at this time to answer these questions and are hampered by the variation inherent in any human population studies (age, sex, ethnicity, history), as well as the diversity of ways in which a TBI, or TBIs, can be sustained. They are mostly inadequate however because of our inability to examine molecular level TBI consequences in the brain during life, restricted as we are to a single timepoint of investigation at autopsy. Thus, we must turn to animal models in which we can profile the brain’s response to injury over time. We have spent years developing and characterizing mouse models of r-mTBI that demonstrate lifelong neuropathological features of human TBI and are thus relevant models in which to generate data that will translate to patients. We have identified novel molecular targets for therapeutic intervention, always relating our findings back to human samples in order to validate their relevance for our human patient population, and have tested new potential treatments in these models. One area which we have not previously examined in our models is the effect of r-mTBI on the endocrine system, through which hormones control and coordinate metabolism, energy levels, growth and development, reproduction, and response to injury and stress. Clinical data, accumulating over the last 10 years, provides evidence for TBI-induced disruption of endocrine function, including hypothyroidism, hypopituitarism, and adrenal insufficiency, and hormone therapy can be an important part of treatment. However, a comprehensive evaluation of the effects of TBI on the endocrine system, including a long-term timecourse of changes and correlation with other TBI outcomes, is lacking in both clinical and preclinical studies. We will tackle this knowledge gap in our proposal, addressing FY21 TBIPHRP IDA Focus Area 1a, by utilizing one of our well-characterized mouse models of repetitive mTBI to increase our understanding of biological factors contributing to long-term outcomes following a brain injury. To achieve this, we will administer our 5-hit r-mTBI model (mTBI every other day for 9 days - with which we have previously reported neurobehavioral and neuropathological outcomes to 24 months post-injury (essentially the mouse lifespan)) or r-sham procedure (no injury but anesthesia of the same frequency and duration) to normal wild type mice. At 2 weeks and 3, 6, 9, and 12 months post-injury/-sham procedure, we will conduct neurobehavioral tests, collect brain interstitial fluid (ISF) and blood samples from the mice, and euthanize them for brain sectioning and neuropathological analyses of markers of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210436
Entities
People
- Fiona Crawford
Organizations
- Roskamp Institute
- United States Army