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Project

Regulation of Bladder Umbrella Cell Paracellular Permeability by Stretch

Funder: National Institute of Diabetes and Digestive and Kidney Diseases

Funding period
USD 90 K
Funding amount
Abstract
PROJECT SUMMARY/ABSTRACT. Tight junctions (TJs) encircle the apical borders of adjacent epithelial cells, and regulate paracellular permeability. The permeability properties of the TJ depend on the expression of transmembrane claudins, which can be cationic or anionic pore-formers or can occlude the paracellular pathway. Critically, TJs must maintain their function in the face of mechanical forces, but how this is accomplished is not well understood. Umbrella cells (UCs) form the outermost layer of the bladder epithelium, and form impermeable TJs, which constitute the urothelial barrier to the pathogens and toxic metabolites in urine. Despite the fundamental importance of the UC TJ in barrier function, and evidence that the UC barrier is disrupted in several diseases of the bladder (e.g., bacterial cystitis, spinal cord injury, and interstitial cystitis), we have limited information about the composition of the UC TJ barrier or the structural and functional changes that allow it to accommodate cycles of filling and voiding. Previous studies from my research group demonstrated that the TJ ring circumscribing each UC doubles in length, and TJ permeability increases when the bladder is filled, and these events are reversed upon voiding. Additionally, claudin expression is altered during the bladder cycle. The mechanisms underlying these changes are unknown. However, I observe that inhibition of exocytosis prevents TJ ring expansion with bladder filling; conversely, inhibition of endocytosis prevents TJ ring contraction upon voiding. I hypothesize that remodeling of the UC TJ depends on changes in the membrane trafficking of claudins, which then modulate TJ permeability. This hypothesis is supported by my preliminary data and will be pursued through two logical aims. In Specific Aim 1, I will determine whether Rab13-dependent exocytosis of pore-forming claudins promotes TJ ring expansion, and increased paracellular permeability during bladder filling. These investigations will employ in vivo biotinylation in combination with exocytosis inhibitors, as well as dominant-active (DA) and dominant-negative (DN) mutants of Rab13, or Rab13-specific shRNAs. Also, I will perform electrophysiological studies to determine if blocking exocytosis prevents the increase in permeability observed with bladder filling. In Specific Aim 2, I will determine whether dynamin-dependent endocytosis of pore-forming claudins leads to TJ ring contraction, and decreased paracellular permeability upon bladder voiding. I will use an in vivo biotinylation internalization assay in conjunction with endocytosis inhibitors and expression of DN-dynamin, to determine if pore-forming claudins are internalized via dynamin-dependent endocytosis. Additionally, I will perform electrophysiological studies to determine if blocking endocytosis, prevents the decrease in permeability observed with bladder voiding. As proposed, this fellowship will provide rigorous training in the field of epithelial cell biology and physiology, which will prepare me for a future career as an independent investigator. Scientifically, the proposed experiments will identify novel pathways of mechanically-regulated TJ dynamics including claudin trafficking to the plasma membrane. Consequently, this proposal will provide a framework to develop therapies targeting pathologies characterized by abnormal claudin expression, and loss of paracellular barrier integrity, such as during cancer metastasis, bacterial cystitis, and interstitial cystitis.

 
44
Projects
USD 51.8 M
Aggregated funding amount
USD 1.4 M
Average funding amount
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Pluripotent stem cell-derived bladder epithelial progenitors for definitive cell replacement therapy of bladder cancer

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Autologous cell engineered bladder augmentation

Medical Research Council to Paolo De Coppi, Martin Birchall, Daniel Wood, Jennifer Southgate, Imran Mushtaq, Massimo Garriboli

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Developing a KMT2D/MLL2-Deleted Preclinical Mouse Model of Bladder Urothelial Cancer

Congressionally Directed Medical Research Programs to David Macpherson

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Androgen Receptor in Bladder Cancer

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Common Mechanisms of Stem Cell Regulation in Bladder Cancer and Regeneration

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Progranulin signaling in bladder cancer

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Generating molecular markers that selectively label urothelial sub-populations

National Institute of Diabetes and Digestive and Kidney Diseases to CATHY LEE MENDELSOHN

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Proliferation and Differentiation of Bladder Epithelial Cells in Regeneration and Malignancy

National Cancer Institute to PHILIP A BEACHY

USD 3,229,708
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Chemoprevention of tobacco carcinogen-induced bladder cancer

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USD 151,690
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Gene expression as possible biomarker in bladder urothelium of patients with ulcerative interstitial cystitis

Japan Society for the Promotion of Science to Osamu NISHIZAWA, Yasuhiko IGAWA, Tetsuya IMAMURA, Tomoaki TANABE

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Mechanisms of epithelial renewal in normal and diseased urinary bladder

National Institute of Diabetes and Digestive and Kidney Diseases to INDIRA U MYSOREKAR

USD 166,717
2007 - 2009
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