Friday, December 27, 2024
12/27/2024
PROJECT SUMMARY Genetic generalized epilepsies (GGE) are the major subtype of epilepsy syndromes, accounting for about 40% of U.S. cases. Contrary to popular belief, over one-third of GGE cases that persist into adulthood live with uncontrolled seizure activity and neurocognitive impairments, negatively impacting quality of life and leading to higher-than-expected risk of death. Despite the urgent need for new treatment options, development of effective anti-seizure medications has largely stalled over the past decade, as research is mainly centered on rodent models that fail to manifest the complex symptomology and recapitulate the polygenic etiology that underlies human GGE. As such, alternative approaches are needed to advance the field of epilepsy research, including animal models that are more congruent to the human condition. The baboon represents one such alternative, as it resembles humans more closely than rodent strains – genetically, physiologically, and (neuroanatomically) – and presents naturally occurring, highly heritable GGE, with strong electroclinical similarities with human epilepsy. Our primary objective in this study is to robustly characterize the genetic and transcriptomic architecture of epilepsy in baboons and develop an in vitro model, based on induced pluripotent stem cell (iPSC)-derived cerebral organoids, that recapitulates molecular signatures observed in human epilepsy. We will achieve this through the following integrated aims: (1) identify epilepsy-risk variants across the baboon genome, including targeted examinations of human candidate gene homologs, and characterize biological pathways enriched with potential risk genes; (2) quantify gene and miRNA expression levels in epileptic and healthy baboon brains through single nuclei RNA sequencing (snRNA-Seq) and identify genetic-transcriptomic associations involving risk variants, such as our recently implicated RBFOX1, as well as wider perturbations in co-expression networks; and (3) generate primary and CRISPR-edited isogenic cerebral organoids derived from epileptic and healthy baboons to assess the effect of RBFOX1 perturbations on the transcriptional landscape and synaptic function, and explore potential mechanisms for restoration of synaptic function in epilepsy. The results of this study will be the first necessary step in establishing a novel in vivo and in vitro preclinical platform for therapeutic discovery that is based on non-human organoids. With a high incidence of new GGE cases in our studied baboon colony, large-scale investigations can be initiated and maintained, allowing for a vertically integrated pipeline from epileptic animal to manipulated organoid systems that can interrogate the etiological architecture of epilepsy from a multi-omic perspective. This includes whole genome sequencing, snRNA-Seq, epigenomic and proteomic profiling, neuroimaging, and electroencephalography, as well as more invasive investigations of the epileptic brain that are not feasible or are limited in human cohorts, creating a unique research platform that can inform, complement, and support findings from human-based epilepsy studies.
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