Prostate cancer is the most common diagnosed male malignancy and the fourth leading cause of cancer in men. There are several driver gene mutations that drive prostate cancer, including TMPRSS2 with ETS family genes, amplification of the MYC oncogene, deletion and/or mutation of PTEN and TP53 and, in advanced disease, amplification and/or mutation of the androgen receptor (AR). We analyzed the RNA abundance of 28 prostate cancer driver genes in 334 prostate cancer patients from the Cancer Genome Atlas (TCGA). We performed T-tests to compare the RNA abundance of these driver genes between different patient groups, as defined by clinical criteria.

Dilated cardiomyopathy (DCM), an idiopathic cardiac disease which causes ventricular enlargement, is one of the most common sources of heart disease in the United States. Electrical mapping technology can be utilized to analyze the speed and directionality, or conduction velocity (CV), of electricity as it travels through the myocardium. We hypothesize that the CV of mice with DCM will be slower than the CV of wildtype (WT) mice, which leads us to conclude that DCM results in arrhythmogenesis. The action potential of the left epicardial ventricle was measured for 15 seconds. The hearts were paced for five seconds at a stimulation frequency of 10 Hz and then at 12 Hz. From the measured action potential, an activation time map was produced and the CV was calculated. The average CV of the DCM+ mice (n = 2) and WT mice (n = 2) paced at a stimulation frequency of 10 Hz, was found to be 0.24552mm/ms and 0.457012mm/ms, respectively. The CV of DCM+ mice (n = 1) and the average CV of WT mice (n = 3) paced at a stimulation frequency of 12 Hz, was found to be 0.260676mm/ms and 0.42203633mm/ms, respectively. In conclusion, these findings demonstrate that mice with dilated cardiomyopathy have a significantly lower CV. This indicates that the heart is likely to develop an arrhythmia. Our data inspires us to study CV in other disease models and procure new surgical procedures for potential clinical implications.

Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder caused by mutations in the DMD gene, which encodes for dystrophin. Dystrophin is a transmembrane protein vital for maintaining muscle membrane integrity. Loss of function of dystrophin results in chronic muscle injury leading to dysregulated inflammation and fibrosis. The Spencer lab showed that global knockout of Osteopontin (Spp1) changes macrophage polarization towards a pro-regenerative type, reduces fibrosis and improves muscle strength. Spp1 is a ubiquitously expressed immunomodulator, is post-translationally modified in many ways, and can bind many different receptors on target cells. Due to its complexity, we aim to understand how specific sources of Spp1 affect DMD progression. To do this, the Spencer lab created dystrophic cell-specific conditional knockout (cKO) mice and used single cell RNAseq to analyze the effect of cell-specific Spp1 ablation on the cellular profile of dystrophic muscle. Ablation of macrophage-derived (Mϕ) Spp1 had a striking effect on the viability of two novel stromal cell subsets that are significantly reduced compared to control, suggesting a paracrine effect of Mϕ Spp1 on stromal cell populations. Nichenet analysis identified a possible mechanism through which macrophage TGFß regulates stromal cell survival. To validate this, we stained Mϕ cKO and control muscle for CD68(+) macrophages and PDGFRA(+) stromal cells and saw areas of overlap, indicating that these two cell types are in close proximity. pSMAD3 staining revealed high TGFß signaling in the same PDGFRA(+) stromal cells. This may indicate that Spp1 is critical for macrophages to maintain stromal cell heterogeneity.

The novel Coronavirus (SARS-CoV-2) responsible for the global COVID-19 pandemic has motivated new strategies to modulate SARS-CoV-2 viral proteins chemically. One such protein is the Coronavirus nonstructural protein 14 (NSP14), which acts as a viral RNA proofreader of SARS-CoV-2, limiting the efficacy of nucleoside analog antiviral drugs. Our research group has made significant progress in the chemical inactivation of NSP14 through novel cysteine reactive small molecules that induce degradation of NSP14. We plan to utilize these small molecules to understand the mechanism behind this degradation. I have synthesized and applied three cysteine reactive molecules, ED1, ED19, and ED24. Chemoproteomic analysis of cells treated with ED1, revealed 7326 total cysteines identified and 1325 sensitive to the compound treated, including known and novel targets. Currently, I plan to use alkyne-containing probe ED24 to identify specific cysteines involved in the degradation of NSP14. We have gained insight into the mechanism underpinning NSP14 by comparing the cysteines labeled by my compounds to those targeted by our prior probes, JC19, and JC17. My future work will allow us to identify on vs. off-target activity, further revealing how these cysteine reactive molecules can rapidly and near completely chemically degrade NSP14. In the future, I hope to apply this approach to traditionally difficult-to-target drug targets.