MHC Class II Transactivator CIITA as a Potential Therapeutic Target for Amyotrophic Lateral Sclerosis
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Leonard, Claudia
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Leonard, Claudia. 2022. MHC Class II Transactivator CIITA as a Potential Therapeutic Target for Amyotrophic Lateral Sclerosis. Master's thesis, Harvard University Division of Continuing Education.Abstract
The incidence of ALS is rising, and with onset of the disease usually occurring around 50-60 years of age, an effective treatment is urgent. Many of the proposed ALS pathogenic mechanisms, including neuroinflammation and oxidative stress, are currently being investigated. However, the effect of antigen presentation on ALS disease progression is unknown. Therefore, my goal for this project is to uncover therapeutic targets for ALS centered on: 1) the expression of MHC class II genes, encoded by the two proteins of the HLA-DR heterodimeric complex in humans and 2) regulation of the cytoskeleton, through genes such as MYBPC2 and RAB4B. The transactivator CIITA regulates the transcription of these MHC class II proteins; a process that contributes greatly to immunocompetence. Based on our recent unpublished findings about the downregulation of the HLA-DR genes in cell lines with ALS-causative mutations, we hypothesize that loss of their master regulator CIITA plays a role in ALS. Since microglia are the immune cells of the central nervous system, we will examine CIITA, HLA-DR, CD74, MYBPC2 and RAB4B expression in the microglial cell line HMC3, as well as in HeLa cells to study the basic science of these ALS-causative proteins. This study, if successful, could lay the groundwork for small molecule drug screening for CIITA agonists as a new strategy for discovering treatments for ALS.Terms of Use
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https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371690
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