# Ca2+ signaling Networks in Health and Disease

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $912,947

## Abstract

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.

## Key facts

- **NIH application ID:** 10514795
- **Project number:** 7R35HL150778-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Mohamed Trebak
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $912,947
- **Award type:** 7
- **Project period:** 2020-02-06 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514795

## Citation

> US National Institutes of Health, RePORTER application 10514795, Ca2+ signaling Networks in Health and Disease (7R35HL150778-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10514795. Licensed CC0.

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