Cellular biology of renal function and disease

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Project Title: Cellular biology of renal function and disease
Principal Investigators (PI): BROWN DENNIS
Project Number: 5P01DK038452-22
Organization: MASSACHUSETTS GENERAL HOSPITAL
 
Project Description:
[unreadable] , OVERALL (provided by applicant): [unreadable] [unreadable] Paradigm-shifting observations on aquaporin 2 (AQP2) and vasopressin receptor (V2R) trafficking, and [unreadable] vacuolar ATPase (V-ATPase) pH sensing and recycling have lead to new hypotheses to be addressed in this renewal. Project I will define VP-dependent and independent regulation of AQP2, and will identify proteins whose interaction with AQP2 is modified by phosphorylation to regulate trafficking. A novel role for AQP2 in regulating actin polymerization via interaction with RhoGAPS will be explored. Use of PDE5 inhibitors and statins to achieve VP-independent urine concentration will be tested as a potential strategy for future treatment of NDI. Project II will examine ligand induced conformational changes of the V2R at varying pH and tonicity using FRET techniques to dissect intra- and intermolecular protein interactions. Association of V2R with accessory proteins during internalization will be defined in cells expressing wild type and mutant V2R. Our novel observation that V2R interacts with the ESCRT protein Alix to accelerate V2R degradation will be pursued in these studies that address the regulation of body fluid homeostasis. Project III will pursue the breakthrough finding that the V-ATPase is an endosomal pH sensor by defining conformational changes in the V-ATPase tail that result in pH-dependent recruitment of small GTPases to membranes. It will identify pH sensitive residues on the luminal domains of the V-ATPase, and use albumin uptake to show relevance of the pH sensing mechanism to proximal tubule function. Project IV will elucidate downstream effectors (PKA, Epac) of soluble adenylate cyclase in modulating V-ATPase recycling and proton secretion in the epididymis, a "model" epithelium in which luminal acidic pH is critical for sperm maturation and storage. It will examine the role of cGMP-induced proton secretion in this tissue, and will address the exciting hypothesis that the V-ATPase is also an extracellular pH sensor that provides feedback control of luminal pH. These studies will allow a better understanding of male fertility, and uncover mechanisms that regulate V-ATPase in acidifying cells in general, including renal intercalated cells. The Microscopy Core B facility has been a major contributor to the success of this PPG. All projects gain considerable added value from extensive intellectual and technical collaborations that characterize our efforts to understand the relationship between cellular signaling, protein trafficking, and the responses of urogenital epithelial cells to their environment. [unreadable] [unreadable] [unreadable]
 
Project Terms:
3,5 cyclic AMP synthetase APS AQP-CD AQP2 protein ATP phosphohydrolase ATP pyrophosphate-lyase (cyclizing) ATPase AVPR2 AVPR2 gene Abbott brand of sildenafil citrate Accounting Actins Address Adenosine Cyclic Monophosphate-Dependent Protein Kinases Adenosine Triphosphatase Adenosinetriphosphatase Adenyl Cyclase Adenylate Cyclase Adenylyl Cyclase Affect Albumins Antidiuretic Hormone Antidiuretic Hormones Aquaporins Autoregulation Bicarbonates Body Fluids Body Tissues Capsid Proteins Carrier Proteins Cell Function Cell Process Cell membrane Cell physiology Cell surface Cells Cellular Function Cellular Physiology Cellular Process Cellular biology Chemotherapy-Hormones/Steroids Clinical Trials Clinical Trials, Unspecified Coat Proteins Collaborations Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cytoplasmic Membrane DI1 Daily Dark Cell Data Degradation Pathway Degradative Pathway Diabetes Insipidus, Nephrogenic Disease Disorder Endocrine Gland Secretion Environment Epididymis Epithelial Epithelial Cells Epithelium FRET Faculty Fecundability Fecundity Feedback Fellowship Fertility Fluorescence Resonance Energy Transfer Funding Future GFAC GTP Phosphohydrolases GTPases Genitourinary Genitourinary system Goals Grant Growth Agents Growth Factor Growth Factors, Proteins Growth Substances Guanosine Cyclic 3',5'-Monophosphate Guanosine Cyclic Monophosphate Guanosine Triphosphate Phosphohydrolases Guanosine, cyclic 3',5'-(hydrogen phosphate) Guanosinetriphosphatases H(+) Pump H+ element HCO3 Homeostasis Hormonal Hormones Hydrogen Carbonates Hydrogen Ions Individual Intercalated Cell Investigation Journals KLK3 KLK3 gene KLKB1 Kidney Lead Ligands Literature Lysosomes Magazine Maturation of Spermatozoa Membrane Methods and Techniques Methods, Other Microscopy Modeling Molecular Monomeric G-Proteins Monomeric GTP-Binding Proteins Nature Nephrogenic Diabetes Insipidus Numbers Organism-Level Process Organismal Process PKA Paper Participant Pathway interactions Patients Pb element Pfizer brand of sildenafil citrate Phosphorylation Physiologic Physiologic Processes Physiological Physiological Homeostasis Physiological Processes Physiology Plasma Membrane Process Programs (PT) Programs [Publication Type] Progress Reports Protein Kinase A Protein Localization Protein Phosphorylation Protein Trafficking Proteins Proton Pump Protons Publications Publishing Range Receptor Protein Recruitment Activity Recycling Regulation Regulatory Protein Renal function Reports, Progress Role Science Scientific Publication Signaling Protein Small G-Proteins Small GTPases Sperm Maturation Stimulus Subcellular Process Subcellular Protein Targeting Subcellular Targeting, Physiological Sum Tail Techniques Testing Therapeutic Hormone Time Tissues Traffickings, Protein Transport Proteins Transporter Protein Urinary System, Kidney Urinary System, Urine Urine Urogenital Urogenital System V-ATPase V-type ATPase V2R VESCL Vasopressin Receptor Vasopressins Vesicle Viagra Viral Coat Proteins Viral Outer Coat Protein WCH-CD Water Channel Proteins Work adenylcyclase aquaporin-2 aquaporin-CD beta-Hypophamine cAMP-Dependent Protein Kinases cGMP cell biology cell type clinical investigation computerized data processing data processing disease/disorder extracellular gene product genetic regulatory protein guanosine 3'5'monophosphate guanosinetriphosphatase heavy metal Pb heavy metal lead human disease inhibitor inhibitor/antagonist insight intracellular protein transport kidney function late endosome male membrane structure mutant novel pathway plasmalemma polymerization programs protein transport receptor recruit regulatory gene product renal response sensor signal processing social role solute success trafficking uptake urogenital system (urinary part) vacuolar ATPase vacuolar H+-ATPase vacuolar membrane H(+)-ATPase water channel water channel of collecting duct water transporter willingness
Project Title: Cellular biology of renal function and disease
Principal Investigators (PI): BROWN DENNIS
Project Number: 5P01DK038452-22
Organization: MASSACHUSETTS GENERAL HOSPITAL
 
Project Categories:
• Natural Sciences > Metabolism & Nutrition > Sugar metabolism
 
Other Information:
Fiscal Year: 1997
Project Start Date: 1 April 1997
Project End Date: 31 March 2012
Administering Institute Or Center: DK
 
Project Funding Information:
Total Funding: $1,703,577
Year Funding Organization Total Funding, $
2008 NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES $1,703,577
Project Title: Cellular biology of renal function and disease
Principal Investigators (PI): BROWN DENNIS
Project Number: 5P01DK038452-22
Organization: MASSACHUSETTS GENERAL HOSPITAL
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Cellular biology of renal function and disease
Principal Investigators (PI): BROWN DENNIS
Project Number: 5P01DK038452-22
Organization: MASSACHUSETTS GENERAL HOSPITAL
 
Project number Project title Organization FY Funding Organization FY Total Cost
2P01DK038452-21CELLULAR BIOLOGY OF RENAL FUNCTION AND DISEASEMASSACHUSETTS GENERAL HOSPITAL2007NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$1,687,713
5P01DK038452-22CELLULAR BIOLOGY OF RENAL FUNCTION AND DISEASEMASSACHUSETTS GENERAL HOSPITAL2008NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$1,703,577
2R37DK042956-16A1Regulation of proton pump trafficking in kidneyMASSACHUSETTS GENERAL HOSPITAL2008NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$370,915
3P01DK038452-23S1CELLULAR BIOLOGY OF RENAL FUNCTION AND DISEASEMASSACHUSETTS GENERAL HOSPITAL2009NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$192,026
5P01DK038452-23CELLULAR BIOLOGY OF RENAL FUNCTION AND DISEASEMASSACHUSETTS GENERAL HOSPITAL2009NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$1,754,686
5R37DK042956-17Regulation of proton pump trafficking in kidneyMASSACHUSETTS GENERAL HOSPITAL2009NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$373,013
3R37DK042956-17S1Regulation of proton pump trafficking in kidneyMASSACHUSETTS GENERAL HOSPITAL2009NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
$99,999
Project Title: Cellular biology of renal function and disease
Principal Investigators (PI): BROWN DENNIS
Project Number: 5P01DK038452-22
Organization: MASSACHUSETTS GENERAL HOSPITAL
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Cellular biology of renal function and disease
Principal Investigators (PI): BROWN DENNIS
Project Number: 5P01DK038452-22
Organization: MASSACHUSETTS GENERAL HOSPITAL
 
Title Abstract Authors Year Rel
Effects of the renal medullary pH and ionic environment on vasopressin binding and signaling. Kidney international. 2008 Dec 74 (12) :1557-67 Zalyapin, Elena A; Bouley, Richard; Hasler, Udo; Vilardaga, Jean-Pierre; Lin, Herbert Y; Brown, Dennis; Ausiello, Dennis A 2008
Association of soluble adenylyl cyclase with the V-ATPase in renal epithelial cells. American journal of physiology. Renal physiology. 2008 Jan 294 (1) :F130-8 Paunescu, Teodor G; Da Silva, Nicolas; Russo, Leileata M; McKee, Mary; Lu, Hua A J; Breton, Sylvie; Brown, Dennis 2008
New insights into structure-function relationships between archeal ATP synthase (A1A0) and vacuolar type ATPase (V1V0). BioEssays : news and reviews in molecular, cellular and developmental biology. 2008 Nov 30 (11-12) :1096-109 Gruber, Gerhard; Marshansky, Vladimir 2008
Alkaline pH- and cAMP-induced V-ATPase membrane accumulation is mediated by protein kinase A in epididymal clear cells. American journal of physiology. Cell physiology. 2008 Feb 294 (2) :C488-94 Pastor-Soler, Nuria M; Hallows, Kenneth R; Smolak, Christy; Gong, Fan; Brown, Dennis; Breton, Sylvie 2008
The phosphorylation state of serine 256 is dominant over that of serine 261 in the regulation of AQP2 trafficking in renal epithelial cells. American journal of physiology. Renal physiology. 2008 Jul 295 (1) :F290-4 Lu, Hua Jenny; Matsuzaki, Toshiyuki; Bouley, Richard; Hasler, Udo; Qin, Quan-Hong; Brown, Dennis 2008
Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury. Kidney international. 2008 Mar 73 (5) :608-14 Zhang, P L; Rothblum, L I; Han, W K; Blasick, T M; Potdar, S; Bonventre, J V 2008
Phosphorylation events and the modulation of aquaporin 2 cell surface expression. Current opinion in nephrology and hypertension. 2008 Sep 17 (5) :491-8 Brown, Dennis; Hasler, Udo; Nunes, Paula; Bouley, Richard; Lu, Hua A J 2008
Bypassing vasopressin receptor signaling pathways in nephrogenic diabetes insipidus. Seminars in nephrology. 2008 May 28 (3) :266-78 Bouley, Richard; Hasler, Udo; Lu, Hua A J; Nunes, Paula; Brown, Dennis 2008
The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Current opinion in cell biology. 2008 Aug 20 (4) :415-26 Marshansky, Vladimir; Futai, Masamitsu 2008
Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell metabolism. 2008 Oct 8 (4) :310-7 Liu, Libin; Brown, Dennis; McKee, Mary; Lebrasseur, Nathan K; Yang, Dan; Albrecht, Kenneth H; Ravid, Katya; Pilch, Paul F 2008
Transepithelial projections from basal cells are luminal sensors in pseudostratified epithelia. Cell. 2008 Dec 12 135 (6) :1108-17 Shum, Winnie Wai Chi; Da Silva, Nicolas; McKee, Mary; Smith, Peter J S; Brown, Dennis; Breton, Sylvie 2008
Acute hypertonicity alters aquaporin-2 trafficking and induces a MAPK-dependent accumulation at the plasma membrane of renal epithelial cells. The Journal of biological chemistry. 2008 Sep 26 283 (39) :26643-61 Hasler, Udo; Nunes, Paula; Bouley, Richard; Lu, Hua A J; Matsuzaki, Toshiyuki; Brown, Dennis 2008
NF-kappaB modulates aquaporin-2 transcription in renal collecting duct principal cells. The Journal of biological chemistry. 2008 Oct 17 283 (42) :28095-105 Hasler, Udo; Leroy, Valerie; Jeon, Un Sil; Bouley, Richard; Dimitrov, Mitko; Kim, Jeong Ah; Brown, Dennis; Kwon, H Moo; Martin, Pierre-Yves; Feraille, Eric 2008
A fluorimetry-based ssYFP secretion assay to monitor vasopressin-induced exocytosis in LLC-PK1 cells expressing aquaporin-2. American journal of physiology. Cell physiology. 2008 Dec 295 (6) :C1476-87 Nunes, Paula; Hasler, Udo; McKee, Mary; Lu, Hua A J; Bouley, Richard; Brown, Dennis 2008
Modification of kidney barrier function by the urokinase receptor. Nature medicine. 2008 Jan 14 (1) :55-63 Wei, Changli; Moller, Clemens C; Altintas, Mehmet M; Li, Jing; Schwarz, Karin; Zacchigna, Serena; Xie, Liang; Henger, Anna; Schmid, Holger; Rastaldi, Maria P; Cowan, Peter; Kretzler, Matthias; Parrilla, Roberto; Bendayan, Moise; Gupta, Vineet; Nikolic, Boris; Kalluri, Raghu; Carmeliet, Peter; Mundel, Peter; Reiser, Jochen 2008