Bryan
Correa Gonzalez
Sponsor: Alexander Nord, Ph.D. MED: Psychiatry & Behav Sci De novo mutations resulting in the loss of one functional gene copy have been associated with the development of Autism Spectrum Disorder (ASD). One such gene is the chromatin remodeler Chd8. Our previously-created mouse model contains a 5 base-pair deletion in Chd8 and results in haploinsufficiency, where the remaining gene copy is not sufficient for normal development and results in ASD-like phenotypes. Emerging technologies like CRISPR-Activation (CRISPR-A) offer potential strategies for mitigating these effects by targeting enhancer or promoter regions of DNA to boost gene expression. Here, we applied CRISPR-A to modulate CHD8 expression in an immortalized mouse cell line. Specific guide RNAs targeting promoter regions of the mouse Chd8 gene were designed. CRISPR dCas9 plasmids were constructed using bacterial cloning techniques and verified via sequencing. These constructs were delivered to mouse neuroblast and fibroblast cells, N2A and NIH/ 3T3 respectively, in culture. 24h post transfection, qPCR will be used to quantitatively measure Chd8 transcript levels. Future steps include testing this system in primary neuronal cultures derived from haploinsufficient mice. This project aims to establish a proof-of-principle for gene activation as a potential therapeutic strategy while enhancing our understanding of how neuronal development is impacted in ASD. Combining Poly ADP-Ribose Polymerase Inhibitors (PARPi) and Androgen Receptor Pathway Inhibitors in Advanced Prostate Cancer
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Bryan Correa Gonzalez
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Treatment of castration resistant prostate cancer (CRPC) has been improved by poly (ADP-ribose) polymerase inhibitors (PARPis) combined with androgen receptor pathway inhibitors (ARPis). However, the majority of CRPC patients are likely to be treated with an ARPi prior to development of castration resistance. This study used cell line models of treatment naïve CRPC, C4-2B, and ARPi resistant cell lines, AbiR and MDVR. Viability assays testing response to combination treatment along with cell morphology show a significant response to combination therapy compared to monotherapies. Our work suggests that prior exposure to ARPis does not preclude response to combination therapy. Additional work suggested a dual response to PARPi monotherapy including apoptosis and a cytostatic, drug-tolerant persistent (DTP) state. We hypothesize that DTP cells facilitate progression and the development of resistance. Whether ARPis synergize with PARPis to promote apoptosis over the DTP state is unclear. Markers of apoptosis, cellular arrest, and replicative stress suggest an increase in the DTP state over apoptosis. Future studies involve analyzing the transcriptome of persistent cells using RNA-seq to better understand the mechanism behind combination treatment. Analyzing the transcriptome of persistent cells may lead to novel therapeutic strategies and promote the efficacy of the ARPi and PARPi combination. UC Davis 36 th Annual Undergraduate Research, Scholarship and Creative Activities Conference 91 The Grieving Brain's Survival Guide Trinity Cortez-Ansley
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UC Davis / MED: Biochem & Molecular Med / 2025
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Bryan Correa Gonzalez