Define Genetic Basis and Pathologic Network of Post-Traumatic Epilepsy Using Collaborative Cross Mice
Abstract
A head injury commonly results in a devastating condition known as post-traumatic epilepsy (PTE), in which individuals develop spontaneous recurrent seizures weeks, months, and years after the head trauma. PTE is hard to treat, often associated with other post-injury complications, and increases the risk of death. Thereby, PTE affects all aspects of an individual s life and places a considerable economic and social burden on society, particularly for military Service Members, Veterans, and their families. However, there is currently no way to predict or prevent PTE after brain injury. Many factors are at play in individuals who develop PTE after a head injury versus those who do not. For example, scientific evidence suggest genetic difference between people largely determines our susceptibility to PTE after brain injury. To study human diseases, scientists commonly use model organisms, like fly, mouse, and rat. However, most existing animal models of PTE and traumatic brain injury (TBI) are limited because they do not replicate the development of post-traumatic seizures or account for the high level of genetic diversity found in the human population. In order to identify novel genetic and biologic basis of PTE, a model research population with a high level of genetic variation is needed. The Collaborative Cross (CC) mice are an innovative genetic reference population of house mouse. They are uniquely designed to mirror the large genetic difference found in humans. The number of genetic variations among CC (~42 million) is three times greater than the human population. Therefore, CC mice show a spectrum of pathogenic phenotypes that are absent in classical inbred mouse strains. This population of genetically stable yet diverse mice provide us with a strong tool to tackle some key challenges in PTE. We hypothesize that the genotypic and phenotypic diversity of CC allows identification of novel models, pathologic markers, and genetic basis of PTE. This knowledge will further our understanding of the causes of PTE and lead to better control of PTE. To achieve these goals, the following aims are proposed. Aim 1: Define extreme PTE responses and its related pathologic network in CC. We plan to first explore extreme seizure responses after a brain injury in CC to identify novel mouse models of PTE. We will monitor the spontaneous immediate, early and late post-traumatic seizures 24/7 using time-locked chronic video-electroencephalography-(EEG)-electromyography (EMG) recording. We will also assess seizure susceptibility using a traditional chemical convulsant-induced seizure. In addition to seizures, other major post-TBI complications including behavior deficits, EEG abnormality, sleep disturbance, neuroinflammation, diffuse axonal injury, tau pathology, and hippocampal sclerosis will be defined to cross-examine their interplay with PTE in the same cohort of CC. Additional information and biological samples from the same population of CC will also be collected, deposited, and available for public access for future studies. Deliverables of Aim 1 are identification of novel inbred mouse models with extreme PTE responses and creation of pathologic network and biospecimens repository of PTE within CC. Aim 2: Identify the genetic loci, candidate genes, and genetic variants that control PTE risk/resilience. The CC captures greater genetic diversity (> 90%) than other reference populations (~30%) and provides a reproducible source of uniform genome-wide genetic variation that can facilitate the identification of novel disease susceptibility alleles. The identification of PTE susceptible and resistant CC will help us design a genetic mapping study to identify the genetic basis of PTE. We will generate, phenotype, and genotype the backcross or F2 population by mating the PTE susceptible and resistant CC. We will perform quantitative trait locus (QTL) mapping to identify the regions on the mouse genome that control PTE risk/resilience.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210212
Entities
People
- Bin Gui
Organizations
- Ohio State University
- United States Army