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My laboratory studies lower urinary tract dysfunctions due to benign prostatic hyperplasia and obstruction (BPH/BPO), radiation cystitis, prostate cancer and spinal cord injury (SCI). We use innovative approaches including telemetric bladder pressure and sphincter activity recordings in mobile rodents to diagnose/characterize BPH-induced BPO or SCI-induced detrusor-sphincter dyssynergia (DSD) and bioluminescence to study prostate tumor growth in vivo.
We were first to demonstrate naturally occurring BPH/BPO in aged rodents and its’ alleviation with the soluble guanylate cyclase (sGC) activator, cinaciguat, a heme mimetic that stimulates cGMP production by nitric oxide-insensitive oxidized/heme-free sGC. CYB5R3 is the reductase that keeps the sGC heme reduced. We developed a CYB5R3 transgenic mouse where we can selectively knockout this reductase in the prostate and/or bladder.
We were also first to directly measure nitric oxide production by bladder urothelial cells using porphyrinic microsensors and utilized mitochondrial targeting of free radical scavengers to protect the bladder when administered prior to irradiation insult—this work won the ASPET-Astellas award in translational pharmacology and contributed to two United States patents. We recently demonstrated the therapeutic benefits of pro-apoptotic p75 neurotrophin receptor inhibitors and pro-growth TrkB/C stimulators in reversing DSD and reducing contused spinal cord glial/collagen scarring to improve hindlimb mobility, respectively.
We are also studying the therapeutic benefits of cinaciguat as a senolytic and senomorphic agent in promoting apoptosis of senescent cells to prevent reoccurrence of prostate tumors as well as the late onset of radiation cystitis. These studies have resulted in a United States provisional patent application.
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