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NBCe1-mediated Regulation of HCO3- is a Novel Mechanism Underlying Metabolic Reprogramming and Cystogenesis

Award Number: K00DK123834
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 ß-cells identified SLC4A4 as one of few unique genes highly expressed in T2DM ß-cells and repressed in non-diabetic ß-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 ß-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 ß-cell metabolism and dysfunction in T2DM. Accordingly, Specific Aim 1 (F99) will test the hypothesis that ß-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $93,982 )
2024	2024	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/8/2024	NON-COMPETING CONTINUATION	$93,982
														Subtotal = $93,982

Issue Date FY: 2023 ( Subtotal = $89,786 )
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/24/2023	NON-COMPETING CONTINUATION	$89,786
														Subtotal = $89,786

Issue Date FY: 2022 ( Subtotal = $87,090 )
2022	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/30/2022	EXTENSION WITH OR WITHOUT FUNDS	$87,090
														Subtotal = $87,090

Grand Total All Awards = $270,858

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NBCe1-mediated Regulation of HCO3- is a Novel Mechanism Underlying Metabolic Reprogramming and Cystogenesis

Award Number: K00DK123834

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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