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Developing a ‘ubiquitous’ toolkit for modulating ion channel expression in health & diseaseKanner, Scott Arthur January 2021 (has links)
Protein stability is critical for the proper function of all proteins in the cell. Ubiquitin is a key post-translational modification that serves as a universal regulator of protein turnover and has emerged as a highly sought-after signal for biological inquiry and drug development. Yet the pervasive role of ubiquitin signaling has given rise to the fundamental challenge of selectively manipulating a widespread signal: current pharmacological and genetic tools that target the ubiquitin-proteasome system (UPS) broadly alter cellular proteostasis with confounding side effects. Ion channels are essential proteins that regulate fundamental cellular properties including; electrical activity, fluid homeostasis, muscle contraction, neuronal firing, gastric acidification, and gene expression. Enhanced or reduced ion channel expression represents a pathological signature for a myriad of disease states, from chronic pain to cardiac arrhythmias, epilepsy, and cystic fibrosis. Although ubiquitin represents a critical mediator of ion channel expression, the inability to precisely manipulate ubiquitin modifications in situ has limited mechanistic insight and opportunities for therapeutic intervention. To address this barrier, I developed a novel nanobody-based toolset to selectively – and bidirectionally – manipulate the ubiquitin status and functional expression of target ion channels for basic study and therapeutic rescue.
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Development of a mouse model of a novel thin lissencephaly variantBelarde, James Anthony January 2021 (has links)
The human neocortex is a highly sophisticated and organized brain structure that is thought to mediate some of the most complex cognitive functions in humans including language and abstract thought. As such, environmental and genetic insults to its normal structure or function can result in devastating neurological conditions including severe epilepsy and intellectual disability. Malformations of cortical development are an increasing collection of disorders that cause neocortical abnormalities due to impaired developmental processes. One recently identified disorder in this class is a thin lissencephaly variant (TLIS) associated with several mutations in the C-terminus death domain of the caspase-2 activation adaptor CRADD (also known as RAIDD). Beyond this, little is known about the mechanism underlying TLIS pathophysiology despite an increasing number of identified individuals suffering from it. In order to better understand this disorder, as well as the normal developmental mechanisms that are impaired in its pathogenesis, I have developed and characterized three murine models by introducing one of a number of different genetic perturbations associated with TLIS. These animal models show behavioral and biochemical abnormalities similar to those seen in human TLIS subjects. Focusing future studies on the developmental processes that underlie differences seen in these mouse models could greatly inform understanding of disease mechanism in humans and assist in the development in therapeutic interventions. My work presented in this dissertation thus effectively establishes a translationally relevant animal model of TLIS.
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