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G protein-coupled receptor kinase 2 (GRK2) has been a thriving therapeutic target for cardiovascular disease treatment since its discovery for desensitizing and downregulating b-adrenergic receptors that are vital to cardiac function. GRK2 inhibition through a variety of methods in animal models of cardiac ischemia and heart failure achieved improvements in cardiac function, hemodynamic function, cardiomyocyte apoptosis, and fibrotic scar size among many other observations. Although GRK2 has been used as a therapeutic tool in multiple studies, its mechanisms of regulation are necessary to understand its role in disease pathogenesis and therapeutic application. This dissertation comprises two projects (1) investigating the microRNA (miRNA) regulation of GRK2 and (2) investigating the impact of loss of dynamic regulation of GRK2 through S-nitrosylation. (1) Candidate miRNAs were selected from miRNA microarray analysis of miRNA differential expression data and bioinformatic prediction. In vitro validation of kshv-miR- K12-3-5p and hsa-miR-181a-5p have shown their ability to bind to the GRK2 3’UTR as well as significantly decrease GRK2 mRNA or protein. The successful regulation of GRK2 through these miRNAs warrant in vivo application and investigation as GRK2-targeting HF therapy in a mouse model of HF. (2) In order to determine the impact of chronic GRK2 overactivity, mice that contained a knock-in mutation of GRK2 Cys340àSer (GRK2- C340S), a site of dynamic inhibitory regulation by S-nitrosylation, were allowed to age >12 months. Loss of S-nitrosylation of GRK2 was sufficient to cause cardiovascular remodeling and dysfunction over time. / Biomedical Sciences

Hypertension affects nearly 1 billion people worldwide and is a leading risk factor for many cardiovascular diseases that in many cases, presents asymptomatically. Neruopilin-1 (NRP1) is a transmembrane receptor found in vascular smooth muscle (VaSMC) that binds to Class 3 Semaphorin (SEMA) ligand SEMA3A. In vitro RhoA inhibition has been observed to be mediated by NRP1 and SEMA3A interactions but its role in VaSMC have yet to be studied. We hypothesize that the ablation of NRP1 from VaSMC will cause the loss of pro-relaxant stimuli and therefore increase vascular tone and blood pressure in vivo. Using transgenic mice models, inducible VaSMC specific deletion of floxed Nrp1 was achieved using an incorporated cre recombinase enzyme knocked into an SM22α allele. Systolic blood pressure (SBP) was measured using a tail cuff method of litter- and sex-matched mice of control (SM22α+/+; Nrp1f/f) and experimental mice (SM22αcre/+; Nrp1f/f). SBP increased significantly in 11-week-old young male mice after 1 week of 4-hydroxy tamoxifen (4-OHT) treatment compared to control mice and baseline levels measured the previous week (146.6 ± 13.4 versus 105.9 ±12.8 and 110.6 ± 9.1, p<0.001 for both comparisons). A return to normotension comparable to baseline and control measurements was observed in experimental mice after sustained SBP elevation at 2, 4, and 6 weeks. While there was variability in the timing of the decline in between the mice, an overall elevation and decline trend was observed. Interestingly, aged female mice at 47.5 weeks showed no difference in SBP after 4-OHT administration when compared to control groups indicating age and gender as possible contributing factors to the effectivity of NRP1 as a pro-relaxant. This study offers NRP1 as an alternative and novel player in our understanding of hypertension and blood pressure homeostasis. / 2026-03-06T00:00:00Z

Viruses are infectious disease- and cancer-causing agents. Viral infection in humans leads to a variety of cytopathic effects. Viral transcription regulators (vTRs) play a central role in human biological processes by modulating host gene expression through direct and indirect methods of binding to nucleic acids making it important to study. Despite the important role of vTRs in human disease, our understanding of their molecular features and functions remains limited. The focus of this study looks at vTR and human transcription factor (hTF) pairs in order to determine how vTRs affect the binding of hTFs to cytokine and cancer gene promoters. In this study we are conducting a pY1H screen using 139 vTR-hTF pairs, 83 cancer promoters, and 41 cytokine promoters. A total of 108 interactions were seen with results highlighting information about viral genome, family, and species. Overall, this study has offered a revolutionary method to study hTFs and vTRs as pairs in a variety of immune and cancer gene promoters to understand more about mechanisms of host gene regulation.