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Interaction between HspA1A, a seventy-kDa heat shock protein, and lipids in stressed cells

Award Number: SC3GM121226
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: 04/15/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Interaction between HspA1A, a seventy-kDa heat shock protein, and lipids in stressed cells - PROJECT SUMMARY HSPA1A is a stress-inducible seventy-kilodalton heat shock protein that plays essential roles in tumor cell survival. This protein also localizes at the cell-surface and the extracellular medium of stressed and cancer cells. HSPA1A-membrane positive tumors are resistant to radiation therapy, show increased invasiveness, and develop distant metastasis, while membrane-bound and extracellular HSPA1A exert both immunostimulatory and immunosuppressive functions. Recent research revealed that HSPA1A's membrane localization depends on its selective interaction with specific lipids and the protein's extracellular transport is mediated by several mechanisms including exosomes, secretory lysosomes, and lipid rafts. However, the trafficking of HSPA1A towards the cell surface, the relationship between membrane-bound and extracellular HSPA1A, and the specific lipid or protein modifications that trigger HSPA1A's re-localization remain unknown. To answer these fundamental questions, we propose to characterize the trafficking mechanism of HSPA1A's membrane translocation by determining the mechanism by which lipid interactions recruit HSPA1A to endosomal pathway. This objective will be achieved by determining the re-localization pattern of HSPA1A in different subcellular compartments after heat shock using subcellular fractionation and imaging, and depleting specific endosomal lipids with drugs or lipid-biosensors. Furthermore, we will determine whether HSPA1A's extracellular transport depends on its membrane localization and binding to specific lipids. To this end, we will delineate the relationship between membrane-bound and extracellular HSPA1A, and then measure extracellular HSPA1A in the presence or absence of the endo/exosomal pathway inhibitors and lipid-biosensors. Lastly, we will characterize the lipid composition alterations and post-translational modifications on HSPA1A that affect its membrane localization. To determine these changes, we will characterize the dynamics of the lipid composition in stressed-cells, using a targeted lipidomics approach, and identify the differentially expressed lipid modifying genes. Additionally, we will determine whether specific post-translational modifications on HSPA1A are responsible for the increased membrane-bound HSPA1A using a targeted proteomics approach. This proposal will provide fundamental knowledge that will form the basis for future interventions to control membrane- associated and extracellular HSPA1A aiming to decrease tumor survival and increase the immune response. Furthermore, this project will train multiple non-traditional and first-generation undergraduate and master level students, and will prepare them for diverse careers in science.


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 = $106,500 )
2024	2024	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	8	4/22/2024	NON-COMPETING CONTINUATION	$95,850
2024	2024	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	8	6/18/2024	NON-COMPETING CONTINUATION	$10,650
														Subtotal = $106,500

Issue Date FY: 2023 ( Subtotal = $106,500 )
2023	2023	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	7	4/28/2023	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2022 ( Subtotal = $106,500 )
2022	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	004	6	6/27/2022	NON-COMPETING CONTINUATION	$10,650
2022	2022	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	003	6	4/8/2022	NON-COMPETING CONTINUATION	$95,850
2022	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	002	5	11/11/2021	COMPETING CONTINUATION	$108,666
2022	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	4	11/11/2021	NON-COMPETING CONTINUATION	-$104,325
2022	2019	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	3	11/11/2021	NON-COMPETING CONTINUATION	-$4,341
														Subtotal = $106,500

Issue Date FY: 2021 ( Subtotal = $106,500 )
2021	2021	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	5	7/1/2021	COMPETING CONTINUATION	$106,500
2021	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	7/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $106,500

Issue Date FY: 2020 ( Subtotal = $104,325 )
2020	2020	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	4	3/25/2020	NON-COMPETING CONTINUATION	$104,325
														Subtotal = $104,325

Issue Date FY: 2019 ( Subtotal = $104,325 )
2019	2019	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	3	3/20/2019	NON-COMPETING CONTINUATION	$104,325
														Subtotal = $104,325

Issue Date FY: 2018 ( Subtotal = $104,325 )
2018	2018	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	2	4/12/2018	NON-COMPETING CONTINUATION	$93,892
2018	2018	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	001	2	5/11/2018	NON-COMPETING CONTINUATION	$10,433
														Subtotal = $104,325

Issue Date FY: 2017 ( Subtotal = $104,325 )
2017	2017	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 NORTH STATE COLLEGE BOULEVARD	FULLERTON	CA	92831	ORANGE	USA	Biomedical Research and Research Training	000	1	4/15/2017	NEW	$104,325
														Subtotal = $104,325

Grand Total All Awards = $843,300

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Interaction between HspA1A, a seventy-kDa heat shock protein, and lipids in stressed cells

Award Number: SC3GM121226

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: 04/15/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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