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Modulation of calcium influx by Orai channel isoforms and pharmaceutical interventions

English title Modulation of calcium influx by Orai channel isoforms and pharmaceutical interventions
Applicant Hediger Matthias A.
Number 204972
Funding scheme Project funding (Div. I-III)
Research institution Abteilung für Nephrologie Medizinische Universitäts-Kinderklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Pharmacology, Pharmacy
Start/End 01.11.2021 - 31.10.2025
Approved amount 812'000.00
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All Disciplines (4)

Discipline
Pharmacology, Pharmacy
Organic Chemistry
Immunology, Immunopathology
Biochemistry

Keywords (7)

calmodulin; Channel inhibitor; Orai1, Orai2, Orai3; SARAF; STIM2; Kinase; SOCE

Lay Summary (German)

Lead
Unsere Studie generiert neue Erkenntnisse über die molekularen Mechanismen der Regulation der Orai-Calciumkanäle und entwickelt darauf aufbauend neue Wirkstoffvorstufen zur Behandlung chronischer Erkrankungen.
Lay summary

Die Calciumkanäle Orai1, Orai2 und Orai3 transportieren Calciumionen in die Zellen und spielen eine wichtige Rolle bei der Signalübertragung in nicht-erregbaren Zellen. Sinkt die Calciumkonzentration im endoplasmatischen Retikulum der Zellen, werden Orai-Kanäle durch STIM-Calciumsensoren aktiviert und die intrazellulären Calciumspeicher werden mit Calciumionen aus dem extrazellulären Raum wieder aufgefüllt. Unsere Studie soll neue Einblicke in die molekularen Mechanismen gewinnen, die die Orai-Kanäle regulieren. Das Projekt ist weiterhin eine Zusammenarbeit mit zwei prominenten Experten auf diesem Gebiet, Stephen Long (Memorial Sloan Kettering Cancer Center, USA) und Nicolas Demaurex (Universität Genf). Gemeinsam mit Stephen Long hoffen wir, hochauflösende Strukturen von Orai-Kanälen im Komplex mit Inhibitoren zu generieren, um anschliessend mittels strukturbasiertem Wirkstoffdesign neuartige Orai Subtyp-spezifische Calciumkanal-Inhibitoren zu generieren. Zusammen mit Nicolas Demaurex werden die positiven Effekte der erzeugten Verbindungen auf die Immunfunktion und andere pathophysiologische Prozesse getestet. Durch die Bündelung dieser Kompetenzbereiche erhoffen wir uns eine solide Basis für die zukünftige Entwicklung neuartiger pharmazeutischer Wirkstoffe zur Behandlung von chronischen Autoimmunerkrankungen, Pankreatitis und Krebs.

Direct link to Lay Summary Last update: 15.10.2021

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
190714 Optogenetic control of the ER calcium store release by a novel ER-localized photoactivated cation channel 01.12.2019 Spark
182272 Intestinal absorption of transition metals in human health and disease 01.02.2019 Project funding (Div. I-III)
180326 The role of mitochondrial carriers in metabolic tuning and reprogramming by calcium flow across membrane contact sites 01.09.2018 Sinergia

Abstract

Store-operated calcium entry (SOCE) is an integral part of cellular calcium signaling in non-excitable cells and it relies on the calcium release-activated channel (CRAC) subunits Orai1, Orai2 and Orai3 located in the plasma membrane (PM) as well as the endoplasmic reticulum (ER) Ca2+ sensors STIM1 and STIM2. In many cell types, including immune cells and pancreatic acinar cells, SOCE is mediated by Orai1 and STIM1. In addition, STIM/Orai isoforms, together with numerous endogenous modulators such as SARAF and CaM, play central roles in fine-tuning SOCE. There are furthermore the less well-studied heteromeric associations of Orai1/Orai3, which are involved in specific physiological and pathological situations. While SOCE controls vital cellular functions, including migration, proliferation, gene expression and apoptosis, its importance for immune function is evident from the immunodeficiency and autoimmunity in patients with mutations in Orai1 and STIM1 genes. In addition, in acute pancreatitis, overactive SOCE is the principal culprit leading to Ca2+ overload in pancreatic acinar cells, resulting in trypsin activation, inflammation and organ failure. STIM and ORAI proteins furthermore play crucial roles in cancer progression. In addition, a recent randomized controlled trial indicates that Orai1 is an important target for the treatment of COVID-19 patients. Indeed, Orai and STIM have been recognized as important drug targets for the treatment of autoimmune diseases, pancreatitis, cancer and COVID-19. Several excellent SOCE inhibitors have emerged, some of which are under clinical investigation. However, in general, they exhibit limitations in terms of Orai-subtype specificity, off-target effects, bioavailability, solubility and metabolic stability. Through this grant application, by combining our expertise in molecular cell physiology, biochemistry and medicinal chemistry, we propose to address the following Specific Aims:Specific Aim 1: Investigating the role of Ca2+/CaM binding to the SOAR and K-rich domains of STIM1 and STIM2 in fine-tuning of SOCE as well as in regulating the ER-PM contacts and studying how SARAF affects the inactivation of STIM2-mediated CRAC currents and SOCE.Specific Aim 2: Generating inhibitors of Orai channels that have optimal solubility, bioavailability, stability and exhibit Orai subtype selectivity, and testing their efficacy in exocrine and immune cells.Our study will bring important new insights into the molecular mechanisms underlying regulation of SOCE that allows intracellular signaling events in non-excitable cells, including cells of the immune system and secretory cells of exocrine tissues. Advanced Orai channel inhibitors will not only be great scientific tools, but also likely serve as novel hit/lead compounds for the development of agents for chronic autoimmune, other immune-related disorders, acute pancreatitis, COVID-19 and cancer.
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