BAYLOR COLLEGE OF MEDICINE INC
Grant: $213,003 - National Institutes of Health - Aug. 20, 2009
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Award Description: 'Detrmine how Caicua modifies the course of SCA1 and to uncover the molecular functions of Ataxin1. ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by expansion of a CAG repeat that encodes glutamine in Ataxin-1. Our studies under the auspices of the parent grant have striven to shed light on the mechanisms of pathogenesis of this disorder and have yielded several key discoveries. First, glutamine-expanded Ataxin-1 interacts with its native partners to cause SCA1. Some of Ataxin-1’s native interactions are augmented by the glutamine expansion while others are decreased, i.e., there is both gain and loss of function. One of these native partners is Capicua, a transcriptional repressor; interactions with Capicua are among those the polyglutamine expansion impairs, and Capicua levels are decreased in the SCA1154Q/+ mice, a model of SCA1 that closely parallels the human disease. Another partner is an ataxin-1 paralog, Ataxin-1Like (Ataxin-1L), which resides in the Ataxin-1 native complex. We found that mice lacking Capicua die by three weeks of age and are neurologically impaired; similarly, mice lacking both Ataxin-1 and Ataxin-1Like die perinatally and are neurologically impaired. Moreover, loss of Capicua causes reduction in Ataxin-1 levels and loss of either Ataxin-1 or both Ataxin-1 and Ataxin-1L cause reduction of Capicua levels. These data led us to hypothesize that (a) Ataxin-1 and Capicua function in a protein complex and require each other for the functional integrity of the complex; (b) SCA1 pathogenesis involves partial loss of Ataxin- 1/Capicua complex function; and (c) Ataxin-1 and Capicua must regulate overlapping target genes and that pursuit of such targets will provide insight into Ataxin-1’s molecular activities in vivo. To test these hypotheses we propose to: (1) Study the effects of decreasing or increasing Capicua levels in the SCA1154Q/+ mice. To this end, we will utilize our existing Capicua+/- mice and a Capicua transgenic mouse that has elevated Capicua levels. We can thus determine whether decreasing Capicua levels worsens pathology and whether increasing Capicua levels mitigates disease; (2) Identify the targets regulated by the Ataxin- 1/Capicua complex by performing chromatin immunoprecipitation followed by sequencing (ChIP-seq) using antisera to Capicua in one experiment and to Ataxin-1 in a parallel experiment. We will then evaluate Ataxin- 1 and Capicua targets to identify any shared regulated genes. ChIP-seq data will also be coupled with gene expression data from Capicua null, Ataxin-1 null, & Ataxin-1; Ataxin-1L doubly null mice in order to determine the in vivo consequences of loss of target regulation. These studies will accelerate our understanding of SCA1 pathogenesis and will for the first time provide a handle on the in vivo molecular functions of Ataxin-1.'
Project Description: As defined in the Award Description field
Jobs Summary: Postdoctoral Associate Performs responsible research work of a complex nature that requires planning, completing, and occasionally supervising limited research projects in accordance with general plans approved by the supervisor. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 20, 2009. Help expand these official descriptions using the wiki below.
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