This proposal describes a 5-year program for the development of an academic career in lower urinary tract physiology. The Candidate has a background in smooth muscle physiology, and completed doctoral training in Pharmacology and Toxicology under the mentorship of Drs. Stephanie Watts and William Jackson (Michigan State University). He then came to the University of Vermont as a Postdoctoral Fellow to begin a path toward an independent research career. He now combines his strengths in smooth muscle physiology and vascular pharmacology to create a novel proposal investigating bladder blood flow as it relates to bladder dysfunction in diabetes. Nearly half of all diabetic patients experience lower urinary tract symptoms (LUTS), which significantly reduce their quality of life. Although ample evidence links impaired bladder blood flow to LUTS, a fundamental gap exists in our understanding of bladder blood flow regulation and its effects on bladder function. The goals of this project are to understand how the unique properties of the urinary bladder vasculature regulate bladder function. Furthermore, this project will investigate if decreased blood flow leads to bladder dysfunction in diabetes, with a specific focus on signaling mechanisms that regulate vessel tone in bladder arterioles. This hypothesis-driven research project will allow the applicant to develop skills in state-of- the art in vitro and in vivo physioogy methods, including electrophysiology, diameter and membrane potential measurements in isolated blood vessels, and in vivo urodynamic measurements, that will provide unprecedented detail into vascular function in the urinary bladder during diabetes. The results could potentially re-frame LUTS treatment to include both vascular and neurological therapeutic interventions. The University of Vermont (UVM) is internationally recognized for its strength in smooth muscle biology, with unique expertise in both vascular and urinary bladder physiology. Mark Nelson, Ph.D. will mentor the Candidate's scientific development. Dr. Nelson is a recognized leader in the field of vascular biology and bladder physiology and has trained numerous postdoctoral fellows and graduate students, many of whom are now established independent investigators. To enhance the Candidate's training, the program enlists the expertise of a mentoring committee, including Drs. Joseph Brayden, George Wellman, Margaret Vizzard and Mark Plante. Dr. Brayden pioneered techniques for the study of vascular smooth muscle membrane potential. Dr. Wellman adds expertise in K+ channel function and electrophysiology. Dr. Vizzard brings substantial experience with bladder research and in vivo conscious cystometry. Dr. Plante is a successful clinical urologist with perspectives on translational science and research. This research environment maximizes the potential for the Candidate to establish a scientific niche from which an academic career can be constructed. This project will facilitate continued technical, intellectual, and professional training of the Candidate, and will assist the Candidate in the establishment of an independent research laboratory at an academic research institution.

Public Health Relevance

Of the estimated 285 million people worldwide with diabetes, nearly 50% report urinary bladder dysfunction. The discomfort, social stigma and financial burdens of bladder dysfunction significantly reduce quality of life for these patients. This projec will discover how alterations in urinary bladder blood flow and vascular contractility affect bladder function, both normally and in diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK103840-02
Application #
9130890
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK-D)
Program Officer
Rankin, Tracy L
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$149,019
Indirect Cost
$11,038
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Tykocki, Nathan R; Heppner, Thomas J; Erikson, Cuixia Shi et al. (2018) Development of stress-induced bladder insufficiency requires functional TRPV1 channels. Am J Physiol Renal Physiol :
Tykocki, Nathan R; Boerman, Erika M; Jackson, William F (2017) Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr Physiol 7:485-581
Tykocki, Nathan R; Bonev, Adrian D; Longden, Thomas A et al. (2017) Inhibition of vascular smooth muscle inward-rectifier K+ channels restores myogenic tone in mouse urinary bladder arterioles. Am J Physiol Renal Physiol 312:F836-F847
Longden, Thomas A; Dabertrand, Fabrice; Koide, Masayo et al. (2017) Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat Neurosci 20:717-726
Heppner, Thomas J; Tykocki, Nathan R; Hill-Eubanks, David et al. (2016) Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling. J Gen Physiol 147:323-35
Moon, Thomas M; Tykocki, Nathan R; Sheehe, Jessica L et al. (2015) Synthetic Peptides as cGMP-Independent Activators of cGMP-Dependent Protein Kinase I?. Chem Biol 22:1653-61
Mingin, Gerald C; Heppner, Thomas J; Tykocki, Nathan R et al. (2015) Social stress in mice induces urinary bladder overactivity and increases TRPV1 channel-dependent afferent nerve activity. Am J Physiol Regul Integr Comp Physiol 309:R629-38
Tykocki, Nathan R; Nelson, Mark T (2015) Location, Location, Location: Juxtaposed calcium-signaling microdomains as a novel model of the vascular smooth muscle myogenic response. J Gen Physiol 146:129-32