The theme of the laboratory (Program in Membrane Biology, PMB) is to understand how membrane transport vesicles interact with accessory proteins (GTPases, SNAREs, kinases) and with the cytoskeleton (microtubules, actin, and PDZ proteins) to modulate cell function via various membrane transport proteins in physiological and pathophysiological conditions. Experimental models used range from in vitro systems using purified proteins and membrane vesicles (endosomes, Golgi, plasma membrane), to transfected cell cultures, to whole animal models including transgenic mice. All projects are interactive and involve cell biological procedures such as confocal and EM-gold immunocytochemistry, real time confocal and TIRF microscopy. In addition, molecular and biochemical procedures are combined with cell biology to provide a multidisciplinary approach to problem solving. The aim of the research is to understand how physiologically-relevant processes of fluid and electrolyte transport across epithelia are regulated at the cell and molecular levels in kidney, the male reproductive tract and other organ systems.
Bouley R, Yui N, Terlouw A, Cheung PW, Brown D Chlorpromazine Induces Basolateral Aquaporin-2 Accumulation via F-Actin Depolymerization and Blockade of Endocytosis in Renal Epithelial Cells. Cells. 2020;9(4):ePub - PMID: 32340337 - PMCID: PMC7226349 - DOI: 10.3390/cells9041057
Battistone MA, Mendelsohn AC, Spallanzani RG, Allegretti AS, Liberman RN, Sesma J, Kalim S, Wall SM, Bonventre JV, Lazarowski ER, Brown D, Breton S Pro-inflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice. J Clin Invest. 2020;130(7):3734-3749 - PMID: 32287042 - DOI: 10.1172/JCI134791
Hoyer FF*, Naxerova K*, Schloss MJ, Hulsmans M, Nair AV, Dutta P, Calcagno DM, Herisson F, Anzai A, Sun Y, Wojtkiewicz G, Rohde D, Frodermann V, Vandoorne K, Courties G, Iwamoto Y, Garris CS, Williams DL, Breton S, Brown D, Whalen M, Libby P, Pittet MJ, King KR, Weissleder R, Swirski FK, Nahrendorf M Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge. Immunity. 2019;51(5):899-914.e7 - PMID: 31732166 - PMCID: PMC6892583 - DOI: 10.1016/j.immuni.2019.10.010
Battistone MA, Spallanzani RG, Mendelsohn AC, Capen D, Nair AV, Brown D, Breton S Novel role of proton-secreting epithelial cells in sperm maturation and mucosal immunity. J Cell Sci. 2019;:ePub - PMID: 31636115 - PMCID: PMC7003979 - DOI: 10.1242/jcs.233239
Cheung PW, Bouley R, Brown D Targeting the Trafficking of Kidney Water Channels for Therapeutic Benefit. Annu Rev Pharmacol Toxicol. 2020;60:175-194 - PMID: 31561739 - DOI: 10.1146/annurev-pharmtox-010919-023654
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Aquaporin (water channel) trafficking
We are dissecting the mechanisms of water channel (aquaporins 1, 2, 4 and 9) trafficking and regulation in epithelial cells from the kidney and male reproductive tract. These channels play a crucial role in maintaining body fluid homeostasis, and the specific functions of diverse organ systems including the eye, ear, brain and reproductive tract.
Vacuolar H+ATPase (proton pump) trafficking and regulation
Specialized proton secreting epithelial cells are involved in acid-base regulation in the kidney and in sperm maturation in the epididymis. We have identified a soluble adenylate cyclase (sAC) as a sensor of extracellular pH and bicarbonate in the epididymis and vas deferens, and are examining the role of this protein in pH sensing by cells in general.
Endocytotic mechanisms in renal tubular cells
Endocytosis of filtered proteins (albumin) is a major function of the renal proximal tubule that is perturbed in disease states, including diabetes. This leads to loss of albumin in the urine. We are using in vitro systems and animal models to explore proximal tubule receptor mediated endocytosis of albumin with the aim of discovering new strategies for treating albuminuria.
pH sensing in endosomes
Endosomes respond to intravesicular acidic pH by recruiting cytosolic coat components that regulate their trafficking. We have recently identified the H+ATPase as an endosomal pH sensor and we are determining its role in coat recruitment and vesicle trafficking in the protein degradative pathway in epithelial cells.
G-protein coupled receptor trafficking and signaling
We are using diverse microscopic (FRET), biochemical, molecular and pharmacological tools to understand how G-protein coupled vasopressin and PTH receptors signal upon ligand binding. These receptors are involved in various critical aspects of fluid and electrolyte balance, mainly via actions on kidney epithelial cells.
Regulation of iron metabolism
This is a complex process that involves many proteins that bind to and transport iron in and out of cells in a highly coordinated manner. Recently, we established a fundamental link between bone morphogenic protein (BMP) signaling and iron metabolism. By studying this complex but important signaling pathway, we hope to shed light on iron dysregulation diseases such as hemochromatosis and anemia of chronic disease.