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Current Research Projects:
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Environmental estrogens are a major interest of the Tulane Center for Bioenvironmental Research. The Principal Investigators in the the Environmental Astrobiology Center have for some years divided their time between environmental astrobiology and women's health, in particular investigation of the cause of interstitial cystitis. As such, women's health issues continue to be an inseparable part of the life of the Center.
The physical continuity and integrated functions of the kidney, ureter and urinary bladder imply that the lining epithelia should share many common differentiated features. But few things could be further from the truth. Differences between the kidney and urinary bladder begin during embryological development as the epidermal ureteral bud ascends to find elements of the metanephric renal mass. Unique features of transitional epithelium lining the bladder are maintained throughout life. Rapid endocytotic recycling of a massive 70% of the apical surface membrane of transitional epithelial cells lining the bladder, which occurs in seconds during contraction due to emptying, is unprecedented in any other tissue.
Our understanding of the mechanisms of endocytotic trafficking of membrane elements has undergone a revolution, as the membrane bound and cytosolic proteins responsible for the fusion of intracellular vesicles have been identified and cloned. The urinary bladder has regrettably been ignored in virtually all tissue surveys of the proteins mediating intracellular vesicle fusion. In our lab, we have reconstituted endosomal fusion in vitro for endosomal vesicles derived from the renal cortex, renal papilla, and urinary bladder. Once again, studies of endosomal fusion in the urinary bladder are documenting dramatic differences between the fusion properties of endosomes derived from various elements of the urinary tract. The first purpose of the current women's health program is to determine the proteins that mediate these unique fusion properties of urinary bladder endosomes.
Further, in infectious and non-infectious models of bladder inflammation, antigens and bacterial products enter the bladder initially by endocytosis into epithelial cells. During induction of bladder inflammation, the endosomal pathway of the epithelial cells is disrupted with marked vacuolization. The second purpose of the current application is to determine if antigenic challenge disrupts endosomal fusion in the urinary epithelium, and to test if pharmacologic inhibition of endosomal fusion decreases inflammation by limiting antigen delivery.
Hypothesis: Urinary bladder endosomes have unique fusion properties.
| Specific Aim Ia: | To determine the structure and function of bladder-specific isoforms of the highly conserved fusion proteins (syntaxins and synaptobrevins/ cellulobrevins) |
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| Specific Aim Ib: | To determine which heterotrimeric G-proteins mediate bladdder endosome fusion. |
| Specific Aim Ic: | Is the unique cytosol-independent fusion of bladder endosomes due to priming? |
Corollary Hypothesis: Urinary bladder endosomal fusion is disrupted
in models of bladder inflammation?
| Specific Aim IIa: | To determine if endosomal fusion is disrupted in models of bladder
inflammation.
I. Non-infectious models of bladder inflammation a. bladder instillation of ovalbumin to sensitized guinea pigs II. Infectious models using bacterial products a. bladder instillation of the E. coli endotoxin lipopolysaccharide
[LPS] |
| Specific Aim IIb: | To determine if agents which inhibit endosomal fusion ameliorate development of bladder inflammation by limiting delivery of exciting antigens in animal and human models. |
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