Wednesday, July 2, 2025 7/2/2025

Ca2+ signaling Networks in Health and Disease

Award Number: R35HL150778
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/06/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Ca2+ signaling Networks in Health and Disease - Project Summary Our studies integrate fundamental biochemical and biophysical basis of Ca2+ channel activity with animal models of human diseases. We seek an understanding of how native channels are constructed, activated and regulated, how they control important functions in physiological systems and how their altered function drives disease. We are focused on the Ca2+ signaling proteins, ORAI, STIM, MCU and NCLX. ORAI channels are encoded by three separate genes (Orai1-3) and activated by the endoplasmic reticulum (ER) Ca2+ sensing proteins STIM (STIM1- 2). ORAI represent a family of highly Ca2+ selective channels in the plasma membrane (PM) of virtually all cells. The founding member of this family, ORAI1 physically interacts with STIM1 in ER-PM junctions, to mediate store-operated Ca2+ entry (SOCE). SOCE is critical in controlling many physiological functions including secretion, migration and proliferation in virtually all cell types. However, the physiological roles of ORAI2, ORAI3 and the mammalian-specific translational variant of ORAI1 called ORAI1α remain poorly understood. ORAI-mediated Ca2+ signals propagate into mitochondria to regulate both bioenergetics, biogenesis and apoptosis. Mitochondrial Ca2+ uptake is decoded within the mitochondrial matrix, effectively coupling PM receptor activation to metabolic activity. Mitochondrial Ca2+ uptake and extrusion are mediated by the mitochondrial Ca2+ uniporter (MCU) and Na+/Ca2+ exchanger (NCLX), respectively. The mechanisms of reciprocal regulation between MCU/NCLX and STIM/ORAI and the convergence of these mechanisms in the control of metabolism, obesity and vascular disease are unknown. Results from our animal models and our compelling in vivo and in vitro data support specific roles for these Ca2+ signaling molecules at the ER-PM-mitochondria nexus, where they regulate cell signaling and metabolism of critical importance in endothelial dysfunction, obesity, hypertension and vascular remodeling. Our studies are aimed at understanding: 1) The fundamental mechanisms of organization, activation and regulation of these Ca2+ channels and their mechanisms of communication; and 2) The role of these Ca2+ signaling proteins in patho/physiology of vascular and metabolic disease. Our studies will provide novel insights into the precise role of these molecules in metabolic and signaling pathways controlling physiology and pathophysiology and will lead to novel avenues for disease therapy.


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: 2025 ( Subtotal = $786,110 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	6	11/27/2024	NON-COMPETING CONTINUATION	$786,110
														Subtotal = $786,110

Issue Date FY: 2024 ( Subtotal = $871,274 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	5	12/18/2023	NON-COMPETING CONTINUATION	$800,149
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	002	5	6/24/2024	NON-COMPETING CONTINUATION	$71,125
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	1/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $871,274

Issue Date FY: 2023 ( Subtotal = $995,652 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	002	4	3/3/2023	NON-COMPETING CONTINUATION	$90,435
2023	2023	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	4	11/18/2022	NON-COMPETING CONTINUATION	$813,922
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	12/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$91,295
														Subtotal = $995,652

Issue Date FY: 2022 ( Subtotal = $821,652 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	12/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$821,652
2022	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	003	3	5/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$490,715
2022	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	002	2	5/23/2022	NON-COMPETING CONTINUATION	-$490,715
2022	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	2	12/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $821,652

Issue Date FY: 2021 ( Subtotal = $928,751 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$92,875
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	2	2/2/2021	NON-COMPETING CONTINUATION	$835,876
														Subtotal = $928,751

Issue Date FY: 2020 ( Subtotal = $944,709 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cardiovascular Diseases Research	000	1	2/6/2020	NEW	$944,709
														Subtotal = $944,709

Grand Total All Awards = $5,348,148

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Ca2+ signaling Networks in Health and Disease

Award Number: R35HL150778

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/06/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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