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Principal Investigator: Matthew Brown
Organization: BROAD INSTITUTE, INC.
Fiscal Year: 2024
Award: $93,982
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
The loss of glucose-stimulated insulin secretion (GSIS) is a critical pathophysiological event precipitating
development of hyperglycemia in Type 2 diabetes mellitus (T2DM). Recent evidence suggests that loss of
GSIS in diabetes is associated with metabolic reprogramming toward reduced mitochondrial function; however
mechanisms underlying these observations remain largely unknown. Recent single cell transcriptomics studies
of human β-cells identified SLC4A4 as one of few unique genes highly expressed in T2DM β-cells and
repressed in non-diabetic β-cells. Slc4a4 encodes for Na+-nHCO3- cotransporter, NBCe1B in the pancreas and
plays a key role in regulating intracellular pH (pHi). Importantly, increased activation of NBCe1 has been
associated with enhanced intracellular glycolysis and impaired mitochondrial function suggesting it may
contribute to loss of GSIS and consequent development of T2DM. Preliminary dissertation studies support this
hypothesis and demonstrate that inhibition of NBCe1B activity in β-cells improves GSIS in vitro and enhances
glucose tolerance in vivo. These cumulative observations led us to develop a doctoral dissertation direction
with an overall objective to characterize the role of NBCe1B as a novel regulator of β-cell metabolism and
dysfunction in T2DM. Accordingly, Specific Aim 1 (F99) will test the hypothesis that β-cell dysfunction in T2DM
is driven by metabolic reprogramming mediated by cellular alkalization through activation of NBCe1B. Given
the critical role of NBCe1 in maintaining systemic pH homeostasis, the F99 uniquely positions me to elucidate
novel mechanisms associated with dysregulation of acid-base balance in the kidney during the K00 phase.
Specifically, the A-isoform of NBCe1 (NBCe1A) functions as the key mechanism of HCO3- reabsorption in the
kidney. Deletion of NBCe1A is associated with metabolic acidosis and cortical cysts within the collecting duct
(CD). Soluble adenylyl cyclase (sAC) has been identified as a HCO3- sensor within the CD. Previous work
demonstrated that impaired NBCe1A-mediated HCO3- reabsorption activates sAC-cAMP/PKA mediated
signaling. Interestingly, persistent cAMP/PKA activation within the CD has also been demonstrated to be a key
mediator of cyst development and proliferation in polycystic kidney disease (PKD). Therefore, the main
objective of my proposed postdoctoral research direction is to characterize the role of NBCe1A as a novel
regulator of cystogenesis through activation of sAC-cAMP/PKA signaling pathway. Accordingly, Specific Aim 2
(K00) will test the hypothesis that impaired NBCe1A-mediated HCO3- reabsorption activates a soluble adenylyl
cyclase-cAMP/PKA signaling cascade in the collecting duct promoting proliferation and cystogenesis in models
of PKD. Together, the F99 and K00 will propel me to achieve my long-term goal to lead an independent
research program in nephrology.
Terms: <21+ years old><3'5'-cyclic ester of AMP><3,5 cyclic AMP synthetase><Acid-Base Balance><Acid-Base Equilibrium><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adenyl Cyclase><Adenylate Cyclase><Adenylyl Cyclase><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Apical><Basic Research><Basic Science><Beta Cell><Bicarbonates><Buffers><C3d Receptors><CD 21 Antigens><CD21><CD21 Antigens><CR2><CR2 Receptors><Causality><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Chemosensitization><Chemosensitization/Potentiation><Clinical Sciences><Co-Transporters><Code><Coding System><Compensation><Complement 3d Receptors><Complement Receptors 2><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Cyst><D-Glucose><Dark Cell><Depressed mood><Development><Dextrose><Diabetes Mellitus><Distal><Duct><Duct (organ) structure><Dysfunction><Environment><Epstein-Barr Virus Receptors><Etiology><Event><Excretory function><Failure><Functional disorder><Genes><Glucose><Glycolysis><Goals><HCO3><Human><Humulin R><Hydrogen Carbonates><Hyperglycemia><Impairment><In Vitro><Inflammation><Insulin><Insulin Cell><Insulin Secreting Cell><Intercalated Cell><Intermediary Metabolism><Intracellular Communication and Signaling><Isoforms><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Diseases><Kidney Urinary System><Lead><MEKs><Maintenance><Maturity-Onset Diabetes Mellitus><Mediating><Mediator><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic acidosis><Metabolism><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Murine><Mus><NIDDM><Nephrology><Nephrons><Nephropathy><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Output><PKA><Pancreas><Pancreatic><Pancreatic beta Cell><Pancreatic β-Cell><Pathway interactions><Pb element><Phase><Physiopathology><Play><Polycystic Kidney><Polycystic Kidney Diseases><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Potentiation><Prevalence><Proliferating><Protein Isoforms><Protein Kinase A><Regular Insulin><Regulation><Renal Disease><Repression><Research><Research Associate><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure of beta Cell of islet><Subcellular Process><T2 DM><T2D><T2DM><Testing><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Uriniferous Tube><Work><absorption><adenosine 3'5' monophosphate><adult onset diabetes><adulthood><biological signal transduction><cAMP><cAMP-Dependent Protein Kinases><causation><cell metabolism><cellular metabaolism><combat><depressed><developmental><diabetes><diabetic><disease causation><excretion><glucose tolerance><heavy metal Pb><heavy metal lead><hyperglycemic><improved><in vivo><in vivo Model><insulin secretion><islet><ketosis resistant diabetes><kidney disorder><maturity onset diabetes><mitochondrial><new approaches><non-diabetic><nondiabetic><novel><novel approaches><novel strategies><novel strategy><pH Homeostasis><pancreas beta cell><pancreas β cell><pancreatic b-cell><pathophysiology><pathway><post-doc><post-doctoral><post-doctoral trainee><preservation><prevent><preventing><programs><renal><renal disorder><research associates><sadness><sensor><social role><solute><symporter><therapeutic evaluation><therapeutic testing><transcriptomics><treatment strategy><type 2 DM><type II DM><type two diabetes><β-cell><β-cells><βCell>