Age dependent abnormalities in the function of urinary tract urothelium and 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 tissue structure and composition. The unifying hypothesis of this proposal is that aging causes changes in the function of the urinary tract and that these changes in turn influence the response of the tissues to pharmacologic manipulations and to pathologic insults. We have been testing this hypothesis by studying changes in ureteral-vesical function with age and disease at the levels of 1) signal recognition; 2) signal transmission; and 3) signal functional response, and have described age dependent changes in endothelin receptors, inhibitory G-proteins, adenylyl and guanylyl cyclases, neuronal nitric oxide synthase (nNOS) and cGMP dependent phosphodiesterase(s). We now plan to determine the mechanism for these age dependent changes, whether other isoforms are regulated with aging, and whether these age-dependent changes affect smooth muscle and/or urothelial function in the urinary tract. We will: 1) identify, localize and characterize age- and sex hormone-dependent changes in the subtype specificity of endothelin (ET) receptors and of their mRNAs in the urinary tract and determine their effect on urinary tract function; 2) determine the effect of age dependent changes in heterotrimeric G-proteins on downstream enzymatic and functional responses of the urinary tract, and determine if manipulation of cytokines, that are known to increase with aging, can change G-protein levels and affect downstream responses; and 3) determine whether age dependent changes in enzymes which regulate cGMP content, including NOS, G-cyclase and cGMP-dependent PDE, affect urothelial and smooth muscle function of the urinary tract. The determination of how age affects the function of the urinary tract and its response 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
Research Project (R01)
Project #
5R01DK038311-23
Application #
6380558
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Nyberg, Leroy M
Project Start
1977-02-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
23
Fiscal Year
2001
Total Cost
$319,106
Indirect Cost
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yono, Makoto; Yamamoto, Yasuhiro; Imanishi, Aya et al. (2008) Differential effects of prazosin and naftopidil on pelvic blood flow and nitric oxide synthase levels in spontaneously hypertensive rats. J Recept Signal Transduct Res 28:403-12
Yono, Makoto; Mane, Shrikant M; Lin, Aiping et al. (2008) Differential effects of diabetes induced by streptozotocin and that develops spontaneously on prostate growth in Bio Breeding (BB) rats. Life Sci 83:192-7
Yono, Makoto; Latifpour, Jamshid; Yamamoto, Yasuhiro et al. (2008) Region and age dependent differences in alpha(1)-adrenergic responsiveness of rat seminal vesicle and vas deferens. Eur J Pharmacol 587:291-5
Yono, Makoto; Yamamoto, Yasuhiro; Yoshida, Masaki et al. (2007) Effects of doxazosin on blood flow and mRNA expression of nitric oxide synthase in the spontaneously hypertensive rat genitourinary tract. Life Sci 81:218-22
Yono, Makoto; Foster Jr, Harris E; Weiss, Robert M et al. (2006) Age related changes in the functional, biochemical and molecular properties of alpha1-adrenoceptors in the rat genitourinary tract. J Urol 176:1214-9
Wheeler, Marcia A; Ayyagari, Rajasekhara R; Wheeler, George L et al. (2005) Regulation of cyclic nucleotides in the urinary tract. J Smooth Muscle Res 41:1-21
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
Yono, Makoto; Foster Jr, Harris E; Shin, David et al. (2005) Molecular classification of doxazosin-induced alterations in the rat prostate using gene expression profiling. Life Sci 77:470-9
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

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