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The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling

Award Number: R35GM131804
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: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling - ABSTRACT/SUMMARY The overarching objective of the proposed research is to understand how eukaryotic cells organize major lipid signaling pathways, and how these do so in a manner that imparts both spatial and temporal specificity, and specificity of biological outcome. The system of interest is phosphoinositide signaling and the general question of how cells functionally channel a rather simple chemical code into a large diversity of biological activities. The experimental goal is to execute a detailed functional analysis of two under-investigated classes of proteins -- the phosphatidylinositol (PtdIns transfer proteins (PITPs) and the oxysterol binding related proteins (ORPs) -- in control of such functional channeling. To that end, two conceptually linked directions will be pursued that: (i) address cell biological, physiological and mechanistic questions related to the activities of yeast Sec14-like PITPs and the structurally unrelated mammalian StART-like Class 1 PITPs, and (ii) how the yeast oxysterol binding related protein (ORP) Kes1/Osh4 functions as a specific antagonist of Sec14-dependent phosphoinositide signaling in yeast and what role ORPs play in neural stem cell biology. The proposed studies will test specific hypotheses that relate to: (i) how fungal and mammalian PITPs bind membranes and exchange their lipid ligands, (ii) the mechanisms by which individual PITPs regulate specific steps of lipid metabolism in yeast and mammals (neural stem cells, melanoma and the obligate intracellular parasite Toxoplasma) to diversify the biological outcomes of phosphoinositide signaling, and (iii) how the oxysterol binding protein (OSBP)-related proteins work against Sec14- dependent PtdIns-4-phosphate signaling in regulating Golgi phosphatidylinositol-4-phosphate signaling. These studies will clarify key unanswered questions regarding the mechanism of function of PITPs, the mechanisms by which both Sec14-like and StART-like PITPs couple lipid metabolism to PtdIns kinase signaling, and more global ramifications of PITP functional interactions with ORPs. A growing number of inherited neurodegenerative and neurodevelopmental diseases, and diseases of proliferative disorders (e.g. cancer), are attributed to derangements in Sec14-like and StART-like PITP activities. Thus, the proposed studies will provide both new and fundamental information that bears directly on molecular mechanisms by which PITPs regulate and organize signal transduction in eukaryotes, and protect mammals from diseases of deranged cell proliferation (cancer), neurodegeneration and type 2 diabetes in humans.


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: 2025 ( Subtotal = $535,709 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	6	5/2/2025	COMPETING CONTINUATION	$535,709
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	5	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $535,709

Issue Date FY: 2023 ( Subtotal = $848,874 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	5	5/26/2023	SUPPLEMENT FOR EXPANSION	$163,965
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	5	4/19/2023	NON-COMPETING CONTINUATION	$684,909
														Subtotal = $848,874

Issue Date FY: 2022 ( Subtotal = $684,909 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	4	6/22/2022	NON-COMPETING CONTINUATION	$68,493
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	4	4/1/2022	NON-COMPETING CONTINUATION	$616,416
														Subtotal = $684,909

Issue Date FY: 2021 ( Subtotal = $814,111 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	3	7/7/2021	SUPPLEMENT FOR EXPANSION	$129,202
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	3	4/13/2021	NON-COMPETING CONTINUATION	$684,909
														Subtotal = $814,111

Issue Date FY: 2020 ( Subtotal = $682,706 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	2	4/17/2020	NON-COMPETING CONTINUATION	$682,706
														Subtotal = $682,706

Issue Date FY: 2019 ( Subtotal = $443,628 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	1	4/22/2019	NEW	$443,628
														Subtotal = $443,628

Grand Total All Awards = $4,009,937

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The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling

Award Number: R35GM131804

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: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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