Age-dependent abnormalities in the function of urinary tract smooth muscle may lead to deterioration in renal structure and function and/or may result in incontinence with its resultant medical, psychological, sociological, and economic implications. These functional changes may result from alterations in regulatory mechanisms or from changes in membrane structure or composition. The unifying hypothesis of this proposal is that aging causes changes in the biochemical and functional properties of urinary tract smooth muscle, and that these changes may in turn influence the response of these tissues to pharmacologic manipulation and pathologic insult. The long-term objective is to determine both how and why age affects the function of urinary tract smooth muscle. To achieve this goal, we will study changes in ureteral-vesical function with age at the level of 1) signal recognition (hormone-receptor complex); 2) signal transmission (transduction of the signal generated by the interaction of an agonist or hormone with a receptor from the outside of the plasma membrane to the inside of the cell where a biochemical and ultimately a physiologic event occurs); and 3) signal functional response (response to the transmitted signal as measured by changes in contractile force). We plan to: 1) define the physiological parameters involved in receptor regulation, i.e., the regulatory effects of gonadal hormones on the receptor-effector system, 2) characterize and localize autonomic and calcium antagonist receptor subtypes 3) determine the regulatory effect of G-proteins in the transduction of the hormone-receptor signal in adrenergic, muscarinic cholinergic, and calcium antagonist receptor systems, 4) determine how changes in membrane structure and composition that occur with aging affect the functional response of urinary tract smooth muscle, 5) determine the role of the second messengers, i.e., cyclic AMP, cyclic GMP, Ca++ and the products of inositol phospholipid metabolism (inositol trisphosphate, IP3, and diacylglycerol, DG) in the age-dependent functional changes of urinary tract smooth muscle, and 6) determine how age-dependent changes in signal recognition and signal transmission affect the functional response to Ca++ and its agonists and antagonists, membrane perturbers, and potassium channel agonists and antagonists. The determination of how age affects the function of urinary tract smooth muscle and the response of the smooth muscle to pharmacologic agents may provide a rationale for the development of new drugs for the treatment of pathologic states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK038311-14
Application #
3483719
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1977-02-01
Project End
1995-08-30
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
14
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Yono, Makoto; Pouresmail, Mehdi; Takahashi, Wataru et al. (2005) Effect of insulin treatment on tissue size of the genitourinary tract in BB rats with spontaneously developed and streptozotocin-induced diabetes. Naunyn Schmiedebergs Arch Pharmacol 372:251-5
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Yono, Makoto; Latifpour, Jamshid; Takahashi, Wataru et al. (2004) Age-related changes in the properties of the endothelin receptor system at protein and mRNA levels in the rat vas deferens. J Recept Signal Transduct Res 24:53-66
Foster Jr, Harris E; Yono, Makoto; Shin, David et al. (2004) Effects of chronic administration of doxazosin on alpha1-adrenoceptors in the rat prostate. J Urol 172:2465-70
Kang, Walter S; Tamarkin, Frank J; Wheeler, Marcia A et al. (2004) Rapid up-regulation of endothelial nitric-oxide synthase in a mouse model of Escherichia coli lipopolysaccharide-induced bladder inflammation. J Pharmacol Exp Ther 310:452-8
Yono, Makoto; Foster Jr, Harris E; Shin, David et al. (2004) Doxazosin-induced up-regulation of alpha 1A-adrenoceptor mRNA in the rat lower urinary tract. Can J Physiol Pharmacol 82:872-8

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