2021 |
Bergeron, Sadie A |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Investigating Functional Development of Neural Circuits Specified by the Gs Homeobox Transcription Factors in Larval Zebrafish @ West Virginia University
Project Summary: Many questions remain about the genetic mechanisms that when gone awry, lead to neuroanatomical and behavioral deficits associated with neurodevelopmental disorders such as ASD that are typically diagnosed years past birth. Identifying these critical gene networks is one key to developing meaningful early diagnostic and therapeutic strategies for the negative symptoms of these disorders. My long-term goal is to characterize causative genetic mechanisms for neurodevelopmental disorders using a combination of model systems approaches, molecular tools, and behavioral and neuroanatomical analyses. The zebrafish provides a unique opportunity as an easily accessible, vertebrate genetic model system with a comparatively ?simple? nervous system, rapid neurodevelopment, many orthologues of human disease-related genes, and defined and tractable behavioral responses to sensory stimuli. They are also a relatively accessible animal model system for students at various educational levels to use. We can begin to study specific classes of neurons based on their molecular identity and function from the moment that they are born in the embryo through adulthood in rapid time compared to other animal models. My previous work revealed for the first time the molecular identity of key interneurons that mediate sensory processing and reflexive control in mouse and zebrafish. Larval zebrafish with ablated gsx1-expressing neurons have altered sensory motor gating, a phenotype we also found in Gsx1 KO mice to link neurons derived from this developmental genetic network to this clinically relevant behavioral paradigm. Aim 1 of this proposal will determine the role that the gs homeobox genes (gsx1 and gsx2) play in specifying these brainstem and other gsx1/2-derrived interneurons in other brain regions through analysis of neuronal differentiation, cell survival, and proliferation combined with sensory-mediated behavior testing of gsx1/2 zebrafish mutants compared to their wild type siblings. The experiments described in Aim 2 will determine the changes in gene expression that occur in the gsx1/2 zebrafish mutant CNS using state of the art transcriptome profiling at different developmental time points in addition to validating already identified putative, disease-relevant target genes for Gsx1 and Gsx2 that we uncovered by mining the literature in the lab as part of several undergraduate and graduate student projects to date. We will be able to perform these experiments and analyze and validate the large amount of data that will be generated under the expert guidance of genomics and bioinformatics core facilities at WVU. As these studies are based on subsets of interneurons with defined molecular identity and critical functions, they will provide insight into the complex genetic etiology of neurodevelopmental disorders in which patients have defects in sensory- processing comorbid. In addition, they will provide an abundance of data that can be utilized to support future student-driven research projects in the lab that align well with our broader goals.
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