Research Projects | Overview
Network analysis of bladder remodeling following obstruction (R01 DK 077195-08)
Integrated quantitative proteomics and transcriptomics analysis of smooth muscle cells exposed to PDGF stimulation identified MYC as a novel master regulator of SMC behavior. Pharmacologic targeting of MYC with novel bromodomain inhibitors attenuated target genes and proteins within the MYC network, and inhibited mitogen-stimulated proliferation of SMC. We are currently investigating the functional significance of the MYC network in smooth muscle remodeling in vivo using smooth muscle-specific conditional MYC deletion. We have also conducted the first RNAseq analysis on bladder tissue from our rodent model of spinal cord injury (see below) to understand the gene expression changes that occur over time following injury. These studies have revealed previously unanticipated signaling pathways that could be targeted to improve bladder control and minimize fibrosis.
The role of neuropilin 2 in smooth muscle contractility (R01 DK104641-02)
Using a combination of genetically engineered mouse models, ex vivo tissue analysis and cell biology we have implicated neuropilin 2 (Nrp2) as a novel inhibitor of smooth muscle contractility and a potential ‘druggable’ target in the urinary tract and gut. This axis is distinct from conventional pathways of muscle contraction/relaxation such as the cholinergic, purinergic and adrenergic axes and therefore may offer new strategies for drug targeting in settings of aberrant contractility e.g. obstruction, underactivity or neurogenic bladder. We are exploring the cellular mechanisms underlying Nrp2-mediated inhibition of contraction and are evaluating candidate small molecule probes of neuropilin 2 that could be used to inhibit function in the setting of obstruction to restore contractility.
Neurogenic bladder evolution and treatment following spinal cord injury (PVA 2909)
Loss of bladder control is one of the most psychologically and socially devastating complications of spinal cord injury. We found that the naturally occurring 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. In further research, we have implicated the adenosine receptor A2B as a dominant mediator of inosine action in the bladder.
Regulation of RTK signaling in bladder cancer progression (R21 CA198722-01)
Epidermal growth factor receptor (EGFR) and c-MET signaling have long been implicated in bladder cancer pathogenesis. Using a bioinformatics strategy, we identified Sh3gl2 as a novel regulator of EGFR and c-MET in bladder epithelium (‘urothelium’). RNAi-based knockdown of Sh3gl2 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.
Research Training in Pediatric Urology (T32 DK060442-14)
Our National Research Service Award (NRSA) Institutional Training grant (T32) for research training in pediatric urology at Boston Children’s Hospital supports the research component of our pediatric urology fellowship program. The overall goals of the program are: (1) to enhance the trainees’ understanding of basic mechanisms of cell physiology and the molecular basis of disease; (2) to teach state-of-the-art, hypothesis-driven research methodology relevant to both basic science and clinical research; and (3) to provide sufficient time and guidance for a mature postdoctoral experience in basic, translational or clinical studies relevant to the trainees’ future clinical careers and academic leadership roles. The fellowship represents a unique combination of outstanding clinical and basic research training within one of the world’s leading centers for academic medicine and biomedical science. It is designed to enable our graduates to establish their own competitive programs of scholarship and research during their careers as academic pediatric urologists. These clinician-scientists can then contribute to understanding the genitourinary system in fundamental terms and to translating basic research findings into clinical applications.