Funding

[RO1 DK135541]  The brain controls the kidney's excretion of salt, its release of the blood pressure controlling protein, renin and its ability to remove blood poisons through filtration, and it is likely that disorders in brain control lead to hypertension and sudden failure of kidney function. Until we can identify the specific nerve cells in the brain which control the kidney, we will not be able make progress in understanding how the brain controls kidney function. The studies proposed in this grant will identify which nerve cells in two parts of the brain (hypothalamus and medulla) actually control kidney function and in doing so will open the way for investigators to map out the brain circuits that control kidney function in health and disease.

[R25 DK095727] A course for renal fellows held at the MDI Biological Laboratory in Bar Harbor, ME, with hands-on research education in fundamental concepts of homeostasis. It exposes nephrology fellows to the classical experiments that form the foundation of renal physiology and nephrology.

[RO1 DK126674]  Purinergic signaling is a prominent dysregulated contractile signaling pathway in diseases of the bladder. While purinergic contractility is minimal in normal human bladder, it increases significantly in bladders of human patients with overactive bladder, diabetic bladder and outlet obstruction. ENTPD1 is a rate-limiting enzyme converting ATP/ADP/AMP sequentially. ENTPD1 controls the kinetics of an agonist cascade (ATP>ADP>adenosine), and hence plays a critical role in the control of purinergic receptor expression and function. We expect this study to substantially advance our understanding on how bladder contraction and relaxation is controlled by ENTPD1 and its associated purinergic signaling. These studies have high potential to introduce novel therapies for human LUTS patients as there are multiple targetable options

[RO1 DK135672]  The L-type voltage-gated calcium channel Cav1.2 is responsible for the excitation-contraction coupling of bladder smooth muscle (BSM), making it an attractive drug target for the treatment of lower urinary tract symptoms (LUTS). Nifedipine, a Cav1.2 antagonist, inhibits BSM contraction. However, trials of nifedipine and other calcium channel blockers (CCBs) for LUTS patients were unsuccessful. On the contrary, cardiologists and epidemiologists have consistently reported that intake of CCBs like nifedipine causes higher voiding frequency and worsen the severity of LUTS in patients. The mechanism of this mystery has never been answered, which hampers its application as a useful drug target for LUTS treatment. We have discovered that ketamine functions as a Cav1.2 antagonist to cause ketamine cystitis - a painful bladder syndrome presenting as frequency, small voids, and incontinence. A complete understanding of this mechanism should answer the longstanding question of why Cav1.2 antagonists are of no benefit for LUTS patients, and potentially leads to novel therapeutics for LUTS treatment.

[RO1 DK125708] Lower urinary tract symptoms (LUTS) affect millions of people and are especially prevalent in the elderly population. LUTS are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. Despite some progress in our understanding of the circuits that control reflex and voluntary urination, significant knowledge gaps remain. An enhanced understanding of how finely tuned and effective neural control over bladder function is achieved is central to efforts directed at developing newer and more targeted treatments for LUTS. The objective in this particular application is to understand which neurons detect, relay and process the bladder distention signal, so that it ultimately becomes integrated into coherent neural control for proper bladder function.

[K99/R00 AG076739]  Early intervention is critical for inhibiting progression of Alzheimer's disease (AD) and related neurodegenerative disorders. Cis phosphorylated Thr231-Pro tau (cis P-tau) has been implicated as an early and pathogenic tau conformation driving neurodegeneration in AD, traumatic brain injury (TBI) and vascular dementia (VaD). The goal of this proposal is to investigate a conserved and early molecular mechanism driving neurodegeneration in both diseases and to evaluate the preclinical therapeutic potential to target this mechanism.