Advanced search options

Advanced Search Options 🞨

Browse by author name (“Author name starts with…”).

Find ETDs with:

in
/  
in
/  
in
/  
in

Written in Published in Earliest date Latest date

Sorted by

Results per page:

You searched for subject:(RAP30). One record found.

Search Limiters

Last 2 Years | English Only

No search limiters apply to these results.

▼ Search Limiters

1. Hogel, Matthew. INVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATION.

Degree: PhD, Department of Pharmacology with Neuroscience, 2012, Dalhousie University

Huntington’s disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which translocates, and accumulates in the nucleus. Nuclear accumulation of N-mHtt has been directly associated with cellular toxicity. Decreased transcription is among the earliest detected changes that occur in the brains of HD patients and is consistently observed in all animal and cellular models of HD. Transcriptional dysregulation may trigger many of the perturbations that occur later in disease progression and an understanding of the effects of mHtt may lead to strategies to slow the progression of the disease. Current models of N-mHtt-mediated transcriptional dysregulation suggest that abnormal interactions between N-mHtt and transcription factors impair the ability of these transcription factors to associate at N-mHtt-affected promoters and properly regulate gene expression. We tested various aspects of these models using two N-mHtt-affected promoters in in vitro transcription assays and in two cell models of HD using techniques including overexpression of known N-mHtt-interacting transcription factors, chromatin immunoprecipitation, promoter deletion and mutation analyses and in vitro promoter binding assays. Based on our results and those in the literature, we proposed a new model of N-mHtt-mediated transcriptional dysregulation centered on the presence of N-mHtt at affected promoters. We concluded that simultaneous interaction of N-mHtt with multiple binding partners within the transcriptional machinery would explain the gene-specificity of N-mHtt-mediated transcriptional dysregulation, as well as the observation that some genes are affected early in disease progression while others are affected later. Our model explains why alleviating N-mHtt-mediated transcriptional dysregulation through overexpression of N-mHtt-interacting proteins has proven to be difficult and suggests that the most realistic strategy for restoring gene expression across the spectrum of N-mHtt affected genes is by reducing the amount of soluble nuclear N-mHtt. Advisors/Committee Members: Dr. Simonetta Sipione (external-examiner), Dr. Jana Sawynok (graduate-coordinator), Dr. Elizabeth Cowley (thesis-reader), Dr. George Robertson (thesis-reader), Dr. Eileen Denovan-Wright (thesis-supervisor), Not Applicable (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).

Subjects/Keywords: Huntington's; Transcription; Repression; Huntingtin; Polyglutamine; Transcriptional Dysregulation; in vitro transcription; N548; ST14A; Dual-luciferase assay; Chromatin Immunoprecipitation; Promoter Deletion; Linker Scanning Mutagenesis; Quantitative PCR; Promoter binding assay; TBP; RAP30

…Overexpression of RAP30 did not recover N-mHtt-mediated transcriptional repression… …139 4.6 Transfection with pCDNA vector containing human RAP30 cDNA led to RAP30 expression… …in N548wt and N548hd cells............................................ 141 4.7 RAP30… …protein was not specifically detected at the CMV promoter .............. 143 4.8 RAP30 protein… …150 4.12 Overexpression of RAP30 and RAP74 protein together did not recover N-mHtt… 

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Hogel, M. (2012). INVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATION. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/15723

Chicago Manual of Style (16th Edition):

Hogel, Matthew. “INVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATION.” 2012. Doctoral Dissertation, Dalhousie University. Accessed December 11, 2019. http://hdl.handle.net/10222/15723.

MLA Handbook (7th Edition):

Hogel, Matthew. “INVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATION.” 2012. Web. 11 Dec 2019.

Vancouver:

Hogel M. INVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATION. [Internet] [Doctoral dissertation]. Dalhousie University; 2012. [cited 2019 Dec 11]. Available from: http://hdl.handle.net/10222/15723.

Council of Science Editors:

Hogel M. INVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATION. [Doctoral Dissertation]. Dalhousie University; 2012. Available from: http://hdl.handle.net/10222/15723

.