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You searched for +publisher:"University of North Carolina" +contributor:("Richardson, Bryan Timothy"). One record found.

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University of North Carolina

1. Richardson, Bryan Timothy. Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins.

Degree: Pharmacology, 2013, University of North Carolina

Cerebral cavernous malformations (CCM) are the second most common class of cerebrovascular brain malformations affecting .1-.5% of the population. The disease is manifested in endothelial cells as lesions of thin, dilated, and leaky capillaries lacking normal blood vessel-stromal interactions. Lesions cause varied symptoms ranging from minor headaches to seizure and hemorrhagic stroke. CCMs can be incurred sporadically or inherited in an autosomal dominant manner from loss of function mutations in one of three genes, CCM1/Krit1, CCM2/OSM, or CCM3/PDCD10. These mutations affect the actin cytoskeleton due to deregulated RhoA/ROCK signaling, which increases stress fiber incidence, reduces endothelial cell barrier function, and decreases angiogenesis in vitro. We demonstrate through global kinome profiling that numerous kinases controlling the actin cytoskeleton are deregulated. Of these, we demonstrate that the RhoA/ROCK effector Lim kinase is overactive and phosphorylates and in activates the actin depolymerizing factor cofilin. Importantly, in vitro CCM phenotypes are rescued with knock down of Lim kinase in CCM protein deficient cells. We further show that a potential molecular mechanism governing the elevated RhoA levels and activity is through the E3 ubiquitin ligase Smurf1, which associates with CCM2 but not CCM1 or CCM3 and is responsible for ubiquitinating GTP bound RhoA. Current cell culture and animal models of CCM have given insight into CCM phenotypes, but the study of patient cells are needed to validate these models and to test potential therapeutics. Thus, we provide proof of principle studies demonstrating the utility of both endothelial progenitor derived endothelial cells and pluripotent stem cells in CCM disease modeling for the ultimate goal of producing a library of patient induced pluripotent stem cells. Overall, our findings elaborate on and provide insight into the complex molecular pathways involved in CCM phenotypes while also making the first steps towards in vitro patient specific CCM disease modeling. Advisors/Committee Members: Richardson, Bryan Timothy, Johnson, Gary.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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

APA (6th Edition):

Richardson, B. T. (2013). Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:6478fcfa-19a8-41df-9bea-f7ca335f9d7c

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Richardson, Bryan Timothy. “Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins.” 2013. Thesis, University of North Carolina. Accessed October 30, 2020. https://cdr.lib.unc.edu/record/uuid:6478fcfa-19a8-41df-9bea-f7ca335f9d7c.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Richardson, Bryan Timothy. “Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins.” 2013. Web. 30 Oct 2020.

Vancouver:

Richardson BT. Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins. [Internet] [Thesis]. University of North Carolina; 2013. [cited 2020 Oct 30]. Available from: https://cdr.lib.unc.edu/record/uuid:6478fcfa-19a8-41df-9bea-f7ca335f9d7c.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Richardson BT. Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins. [Thesis]. University of North Carolina; 2013. Available from: https://cdr.lib.unc.edu/record/uuid:6478fcfa-19a8-41df-9bea-f7ca335f9d7c

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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