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Intracellular Functions of the Bioactive Sphingolipid Metabolites Sphingosine and Sphingosine-1-phosphate

Award Number: R01GM043880
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY AND RELEVANCE The long-term goals of this project are to define the intracellular functions of the bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and sphingosine. Most of the known actions of S1P, produced intracellularly from sphingosine by two closely related sphingosine kinases, SphK1 and SphK2, are initiated by signaling through S1P receptors. However, lower organisms have similar evolutionary conserved sphingolipid metabolic enzymes and although their sphingolipid metabolites have important functions, they do not have S1P receptors. Based on published and exciting preliminary results, our overarching hypothesis is that recruitment of SphK1 to sphingosine-containing vesicles and conversion of sphingosine to S1P plays a critical role in membrane trafficking, formation and functions of membrane contact sites between the endoplasmic reticulum and late endosomes and lysosomes. These membrane contact sites are highly regulated regions of close membrane apposition between organelles that serve as platforms for transfer and metabolism of lipids, including cholesterol and sphingolipids, calcium homeostasis, and to ensure inter-organellar communication. To test this concept, we propose the following specific aims: Aim 1. Identify the key steps in endocytic trafficking and autophagic fluxes that rely on sphingosine to S1P conversion by SphK1; Aim 2. Evaluate the role of the sphingosine/SphK1/S1P axis in regulation of ER-membrane contact sites and consequently on cholesterol and sphingolipid metabolism; Aim 3. Determine the molecular mechanisms by which sphingolipid metabolites regulate membrane trafficking and membrane contact sites and identify their intracellular targets. This proposal will utilize several innovative technologies, including cutting edge electron microscopy and systems-level live cell multispectral fluorescence-based spectroscopy imaging, as well as trifunctional sphingosine click chemistry and state of the art sphingolipidomic mass spectrometry. The new conceptual groundwork in this proposal will alter the view of the enigmatic nature of sphingolipid metabolite signaling and will reveal their ancient but understudied intracellular roles in regulation of membrane dynamics and contact sites with the endoplasmic reticulum as sensors that integrate cell growth signals and coordinate cholesterol and sphingolipid metabolism. This should also provide deeper understanding of how perturbations of these fundamental biological processes contribute to human diseases. !


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: 2023 ( Subtotal = $367,436 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	31	11/15/2022	NON-COMPETING CONTINUATION	$330,692
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	31	2/13/2023	NON-COMPETING CONTINUATION	$36,744
														Subtotal = $367,436

Issue Date FY: 2022 ( Subtotal = $349,625 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	30	5/17/2022	NON-COMPETING CONTINUATION	$36,755
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	30	11/3/2021	NON-COMPETING CONTINUATION	$330,801
2022	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	29	11/2/2021	NON-COMPETING CONTINUATION	-$17,931
														Subtotal = $349,625

Issue Date FY: 2021 ( Subtotal = $435,629 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	29	11/11/2020	NON-COMPETING CONTINUATION	$392,066
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	29	3/12/2021	NON-COMPETING CONTINUATION	$43,563
														Subtotal = $435,629

Issue Date FY: 2020 ( Subtotal = $405,509 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	004	28	5/20/2020	SUPPLEMENT FOR EXPANSION	$30,580
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	28	12/12/2019	COMPETING CONTINUATION	$374,929
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	003	28	5/8/2020	COMPETING CONTINUATION	$49,063
2020	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	27	5/8/2020	NON-COMPETING CONTINUATION	-$49,063
2020	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	27	12/11/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,509

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	27	3/7/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $350,750 )
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	27	3/22/2017	NON-COMPETING CONTINUATION	$315,675
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	27	8/7/2017	NON-COMPETING CONTINUATION	$35,075
														Subtotal = $350,750

Issue Date FY: 2016 ( Subtotal = $350,750 )
2016	2016	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	26	3/22/2016	NON-COMPETING CONTINUATION	$350,750
														Subtotal = $350,750

Issue Date FY: 2015 ( Subtotal = $350,750 )
2015	2015	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	25	3/26/2015	NON-COMPETING CONTINUATION	$350,750
														Subtotal = $350,750

Issue Date FY: 2014 ( Subtotal = $350,750 )
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	24	5/5/2014	COMPETING CONTINUATION	$350,750
														Subtotal = $350,750

Issue Date FY: 2002 ( Subtotal = $287,391 )
2002	2002	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Cell Biology and Biophysics Research	000	13	3/7/2002	NON-COMPETING CONTINUATION	$287,391
														Subtotal = $287,391

Issue Date FY: 2001 ( Subtotal = $320,315 )
2001	2001	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cell Biology and Biophysics Research	000	11	2/12/2001	NON-COMPETING CONTINUATION	$320,315
														Subtotal = $320,315

Issue Date FY: 2000 ( Subtotal = $282,649 )
2000	2000	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cell Biology and Biophysics Research	000	10	2/11/2000	NON-COMPETING CONTINUATION	$282,649
														Subtotal = $282,649

Issue Date FY: 1999 ( Subtotal = $274,943 )
1999	1999	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cell Biology and Biophysics Research	000	9	2/19/1999	COMPETING CONTINUATION	$274,943
														Subtotal = $274,943

Issue Date FY: 1998 ( Subtotal = $101,639 )
1998	1998	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cell Biology and Biophysics Research	001	8	6/19/1998	SUPPLEMENT FOR EXPANSION	$101,639
														Subtotal = $101,639

Grand Total All Awards = $4,228,136

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Intracellular Functions of the Bioactive Sphingolipid Metabolites Sphingosine and Sphingosine-1-phosphate

Award Number: R01GM043880

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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