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Ion Channels and Signaling Mechanisms in T Lymphocytes

Award Number: R37GM045374
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1991
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Ion Channels and Signaling Mechanisms in T Lymphocytes - PROJECT SUMMARY Signaling through store-operated Ca2+ channels (SOCs) is critical for many physiological processes including immune cell activation and differentiation. Accordingly, the loss of SOC function leads directly to a lethal severe combined immunodeficiency syndrome in humans. SOCs are activated by the depletion of Ca2+ from the endoplasmic reticulum (ER), which causes the ER Ca2+sensor STIM1 to accumulate at ER-plasma membrane (PM) junctions where it binds and activates Orai1, the pore-forming subunit of the Ca2+release- activatedCa2+(CRAC)channel,triggeringCa2+entryintothecell.Ourlong-termgoalistounderstandin molecular detail the underlying mechanisms that control Ca2+ influx through CRAC channels. We have developed a number of new approaches to tackle these issues, including single-molecule tracking of STIM1 and Orai1, gene editing with CRISPR/Cas9 to label and mutagenize endogenous proteins, tandem concatemers of Orai1 that allow subunit-selective mutagenesis of the CRAC channel, and single-molecule FRET to probe conformational dynamics in a highly defined in vitro system. Over the next five years, we will apply these approaches to understand CRAC channel regulation in three areas. First, we aim to understand the mechanisms of native STIM1 and Orai1 localization and interaction at ER-PM junctions. Nearly all we know about the SOC mechanism is based on heterologous high-level overexpression of STIM1 and Orai1, which is likely to override many important regulatory mechanisms involving low amounts of accessory proteins. We will exploit gene editing techniques to label and modify endogenous STIM1 and Orai1 and study the factors that control the initial trapping of STIM1 by the PM, the residence time of Orai1 in junctions, and the stoichiometry and interaction kinetics of STIM1 and Orai1 at native junctions. Second, we will extend mechanistic studies of Ca2+-dependent inactivation (CDI), the predominant mechanism for feedback inhibition of CRAC channels. By subunit-selective mutagenesis of hexameric Orai1 concatemers we will characterize the interactions of STIM1 with the II-III intracellular loop and selected pore residues of Orai1 that drive conformational changes underlying COl. The third and major focus will be to identify the dynamic conformational changes that underlie activation of STIM1 and Orai1. By measuring single-molecule FRET of labeled STIM1 and Orai1 in vitro, we will identify the structures that keep STIM1 inactive and how they rearrange after store depletion to activate STIM1. The single-molecule approach will be widely applied to other questions such as the stoichiometry, dynamics and conformation of STIM1 binding to Orai1 as well as the conformational changes leading to Orai1 pore opening and the effects of purified accessory proteins thought to modulate STIM-Orai interactions in living cells. These studies have the potential to resolve many of the most difficult and important issues related to SOC activation, and may suggest new strategies for modulating calcium signals to provide new treatments for autoimmune and immunodeficiency syndromes.


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 = $0 )
2024	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	31	12/3/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $640,956 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	31	6/28/2021	NON-COMPETING CONTINUATION	$640,956
														Subtotal = $640,956

Issue Date FY: 2020 ( Subtotal = $640,956 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	30	7/15/2020	NON-COMPETING CONTINUATION	$640,956
														Subtotal = $640,956

Issue Date FY: 2019 ( Subtotal = $640,956 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	29	6/24/2019	NON-COMPETING CONTINUATION	$640,956
														Subtotal = $640,956

Issue Date FY: 2018 ( Subtotal = $640,956 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	28	6/25/2018	NON-COMPETING CONTINUATION	$640,956
2018	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	27	11/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$14,196
2018	2016	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	26	11/11/2017	EXTENSION WITH OR WITHOUT FUNDS	-$14,196
														Subtotal = $640,956

Issue Date FY: 2017 ( Subtotal = $640,956 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	27	8/16/2017	EXTENSION WITH OR WITHOUT FUNDS	$640,956
2017	2016	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	26	2/15/2017	EXTENSION WITH OR WITHOUT FUNDS	$366
2017	2015	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	25	2/15/2017	NON-COMPETING CONTINUATION	-$366
														Subtotal = $640,956

Issue Date FY: 2016 ( Subtotal = $604,675 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	26	6/24/2016	EXTENSION WITH OR WITHOUT FUNDS	$604,675
														Subtotal = $604,675

Issue Date FY: 2015 ( Subtotal = $604,675 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	25	6/29/2015	NON-COMPETING CONTINUATION	$604,675
														Subtotal = $604,675

Issue Date FY: 2014 ( Subtotal = $604,675 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	24	5/28/2014	NON-COMPETING CONTINUATION	$604,675
														Subtotal = $604,675

Issue Date FY: 2013 ( Subtotal = $583,511 )
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	23	6/20/2013	NON-COMPETING CONTINUATION	$583,511
														Subtotal = $583,511

Issue Date FY: 2012 ( Subtotal = $609,814 )
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	22	7/27/2012	COMPETING CONTINUATION	$609,814
														Subtotal = $609,814

Grand Total All Awards = $6,212,130

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Ion Channels and Signaling Mechanisms in T Lymphocytes

Award Number: R37GM045374

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1991

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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