Browsing by Subject "mitochondrial dynamics"
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Item Open Access Effects of mitochondrial dynamics genes, fzo-1 and drp-1, on dopaminergic neurodegeneration induced by environmental exposure in Caenorhabditis elegans, as a model of Parkinson’s disease(2015-05-30) Hall, SamanthaParkinson’s disease (PD) is caused by degeneration of the dopaminergic neurons; environmental toxicants are hypothesized to play a role in PD etiology. Environmental toxicants can cause mitochondrial dysfunction through mitochondrial DNA (mtDNA) damage and production of reactive oxygen species. Serial ultraviolet C (UVC) radiation causes an accumulation of mtDNA damage and 6-hydroxydopamine (6-OHDA) causes loss of dopaminergic neurons. Mitochondrial dynamics, or fusion and fission of the mitochondria, are important processes in mitigating mitochondrial dysfunction. The fzo-1 and drp-1 genes in Caenorhabditis elegans are orthologs for human Mfn1/2 and Drp1 and are involved in mitochondrial fusion and fission, respectively. I tested the hypothesis that deletion mutant strains for these two genes would show increased neurodegeneration after environmental damage, relative to the wild-type control strain, due to the lack of normal mitochondrial dynamics. Unexpectedly, both the fzo-1 and drp-1 were protected against 6-OHDA-induced neurodegeneration relative to wild-type. The fzo-1 knockout underwent complete larval arrest after UVC exposure, suggesting that mitochondrial fusion is necessary for recovery after mtDNA damage. The drp-1 mutant showed slightly more neurodegeneration than wild-type after UVC exposure at the 10 J/m2 dose, but not the 7.5 J/m2 dose. These results highlight the significance of mitochondrial dynamics and gene-environment interactions in dopaminergic neurodegeneration and PD etiology.Item Open Access Functional screening to define apoptosis-inducing precision cancer therapies(2018) Anderson, GraceCancer is a diverse set of diseases characterized by genetic and epigenetic alterations that permit growth across diverse environmental contexts. The last decade has led to an explosion of sequencing efforts to define the molecular drivers of proliferation across cancers. This effort has led to the development of small-molecule inhibitors that can block oncogenic drivers and the signaling pathways driving growth. These so called “targeted therapies” have led to better progression-free survival in patients. Despite this early success, it has become clear that with few exceptions, all patients treated with targeted therapies will ultimately relapse. Thus, there is an imminent need to define combination strategies that can be employed to suppress intrinsic or acquired resistance in cancer. Here, we combine functional screening approaches, both pharmacological and genetic, to define apoptosis-inducing precision cancer therapies. Specifically, we utilize a pharmacological screening approach to uncover that breast cancers rely on Mcl-1 and Bcl-XL for survival, and that we can leverage mTOR’s translational control over Mcl-1 to induce apoptosis in PIK3CA mutant breast cancers. Additionally, we utilize CRISPR-Cas9 loss-of-function screening to define the landscape of therapeutic cooperativity in KRAS -driven cancers across diverse tissue types. Further, we leverage this landscape to define principles to rationally design combination therapies to suppress resistance. Lastly, in an effort to define targeted therapeutic strategies for cancers that lack traditional oncogenic drivers, we utilized a pharmacological screening approach to define vulnerabilities associated with dysregulated mitochondrial dynamics proteins in cancer. Collectively, our work has demonstrated the power of functional screening approaches to define apoptosis-inducing anti-cancer precision therapies that combat intrinsic and acquired resistance.