Researcher | Research Overview
I am a cell biologist and biochemist, with over 20 years experience in studies related to fundamental mechanisms of urologic disease. Research in my laboratory is focused on deciphering the molecular processes that regulate growth, differentiation and pathologic remodeling in the urinary tract, in both benign and malignant conditions, as outlined below.
- We have implicated neuropilin 2 (Nrp2) as a potential ‘druggable’ target for restoration of bladder muscle contractility in the setting of decompensated bladder function following outlet obstruction. Clinically, no effective treatment exists to increase contractility of the underactive bladder in patients. Using a mouse model of bladder outlet obstruction, genetic ablation of Nrp2 during the decompensation phase was associated with sustained contractility. Moreover, evaluation of human patients with obstruction revealed that those displaying compensated bladder function had lower expression of NRP2 in bladder tissue compared to obstructed patients in whom bladder function was decompensated, consistent with the findings from our mouse model. We are continuing to characterize candidate small molecule inhibitors of neuropilin 2 that could be used to inhibit function in the setting of obstruction to restore contractility. Funding for this project is pending (R01 DK104641-01A1).
- In a separate line of investigation, we have demonstrated that the purine nucleoside inosine exerts profound effects on bladder function following spinal cord injury. When tested in both prevention and intervention regimens in a rat model of spinal cord injury, chronic inosine treatment led to attenuation of neurogenic detrusor overactivity as assessed by cystometry. Evaluation of underlying mechanisms suggested that the primary impact of inosine on the bladder was neuroprotective, but that inosine also modulated sensory neurotransmission, at least in part by attenuating pathologic upregulation of TRPV1. These findings were published in November 2015. Ongoing studies are focused on the molecular mechanisms underlying the beneficial effect of inosine on overactivity.
- In 2014, we published the first integrated quantitative proteomics and transcriptomics analysis of bladder smooth muscle cells in Cell Communication and Signaling. This study validated previous work from our group implicating the AP-1 transcriptional complex as a regulator of smooth muscle cell growth and migration but also revealed MYC as a novel ‘master regulator’ of smooth muscle cell behavior. We have proceeded to determine the functional significance of the MYC-centric network in bladder smooth muscle, and have demonstrated that pharmacologic targeting of MYC with novel bromodomain inhibitors currently undergoing clinical evaluation, leads to attenuation of MYC network target genes and proteins, as well as inhibition of mitogen-stimulated proliferation of smooth muscle cells. The demonstration of AP-1 and MYC as putative therapeutic targets in conditions characterized by fibroproliferative expansion of hollow organs such as the bladder formed the basis of the competitive renewal of our R01 (DK077195), which was funded on the first submission in August 2015. Current studies are employing a small molecule inhibitor of AP-1 to mitigate pathologic remodeling in the bladder wall secondary to spinal cord injury.
- Bioinformatics analysis conducted in our group identified the gene Sh3gl2/endophilin A1 as highly enriched in urothelium. Subsequent validation demonstrated progressive loss of Sh3gl2 with bladder cancer progression in humans, and implicated Sh3gl2 as a novel regulator of kinase activity in urothelial carcinoma. Silencing of Sh3gl2 using RNA interference technology led to increased proliferation in vitro and as xenografts in vivo, and was associated with increased activation of the EGFR, Src-family kinases and STAT3. Ongoing studies are investigating the utility of Sh3gl2 as potential biomarker for sensitivity to EGFR- and MET-targeted kinase inhibitors in urothelial carcinoma.
These studies relate to the mechanisms underlying pathologic remodeling of the bladder wall under conditions of urinary tract obstruction. Their ultimate goal is to identify critical signaling nodes that could be targeted for therapeutic benefit.
Researcher | Research Background
Rosalyn Adam received her PhD from the University of Southampton in the UK. She completed a postdoctoral fellowship at Boston Children's Hospital.