Project Details
Description
Project Summary
Spatially and temporally precise Ca2+ signals control a vast spectrum of cellular functions including contraction,
secretion, transcription, and growth. These signals are mediated by the coordinated function of Ca2+ sensors
and Ca2+ channels. STIM proteins in the endoplasmic reticulum (ER) are luminal Ca2+ sensors in the endoplasmic
reticulum (ER) that physically couple to highly Ca2+-selective plasma membrane Orai channels, through an
extraordinarily dynamic inter-membrane ER-PM junctional coupling process, to generate "store-operated" Ca2+
signals. Dysregulation of STIM/Orai expression is associated with a range of disorders including renal fibrosis,
Idiopathic pulmonary fibrosis, immune deficiency, muscle weakness, skin dysplasia, and cancer. The proposed
studies address the crucial unsolved questions of how STIM proteins undergo activation, what is the molecular
basis of coupling between the distinct STIM and Orai isoforms to generate Ca2+ signals, and what is the
pathophysiological role that the STIM/Orai pathway in cellular remodeling in disease, in particular, in the
mediation of fibrosis, a major feature in multiple chronic diseases leading to global morbidity. Understanding this
fundamental signaling mechanism provides critical new information to generate pharmacological tools to modify
Ca2+ signals and alleviate diseases of cellular growth and remodeling. Genetic alterations giving rise to gain or
loss of function of STIM and Orai proteins lead to severe immunological, muscular, skin, and neural deficits in
humans, and provide critical molecular insights into the structure/function of STIM/Orai proteins.
To deepen our understanding of this critical signaling pathway, the project goals focus on: (1) Investigating the
mechanisms underlying STIM protein activation by Ca2+ store-sensing or temperature change, and the precise
molecular coupling of STIM proteins to Orai channels, focusing on the highly distinct STIM and Orai isoforms,
and utilizing precise molecular/genetic probes, imaging technology, and gene-deleted cell lines and animal
models: (2) Studying how the small molecule 2-aminoethyldiphenyl borate (2-APB) specifically modulates
STIM/Orai isoforms, using genetically-encoded and optogenetically/chemogenetically applied Ca2+ probes
tagged onto STIM and Orai proteins to monitor cytosolic Ca2+ signals mediated by STIM/Orai, and exploring how
2-APB provides crucial information on STIM-mediated clustering of Orai channels and controls local junctional
Ca2+ signals, advancing our mechanistic understanding and the development of small molecules targeting the
STIM/Orai pathway; (3) Examining how STIM/Orai-mediated calcium signals regulate fibrosis in both cellular and
animal model systems, focusing on how the STIM1/Orai2 isoform pathway can be modified to regulate the
process of fibrosis, determining transcriptomal changes related to STIM-specific Ca2+ signal generation, and
utilizing a novel STIM-specific inhibitory peptide, Orai3-M4x, to regulate cell remodeling. Overall, the program of
study seeks to understand the fundamental STIM/Orai signaling pathway that has enormous potential in
alleviating a spectrum of pathological states mediated by cellular growth and tissue remodeling.
Status | Active |
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Effective start/end date | 9/10/24 → 8/31/25 |
Funding
- National Institute of General Medical Sciences: $417,000.00
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