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Directing Membrane Function with Inositol Lipids in Health and Disease

Award Number: R35GM119412
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: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Directing Membrane Function with Inositol Lipids in Health and Disease - PROJECT SUMMARY/ABSTRACT The plasma membrane (PM) is a bustling hub of transport, signaling and structural functions that sustain life at the cellular level. Failure to appropriately choreograph these parallel functions contributes to the pathogenesis of many diseases. Selective regulation of PM function relies on the cytosolic leaflet phosphoinositide (PPIn) lipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. PI(4,5)P2 is a master regulator, recruiting and/or activating scores of proteins controlling PM permeability, vesicular traffic, cytoskeletal assembly and receptor-driven signaling. Human diseases from cancer to rare monogenic disorders are known to be associated with aberrant PI(4,5)P2 levels, which result from disrupted PI(4,5)P2 synthesis or breakdown. That said, the sheer number of PI(4,5)P2-regulated functions has made it challenging to identify which functions contribute to disease phenotype, let alone attempt therapeutic intervention. Therefore, the long-term goal of the lab's research is to develop a detailed, mechanistic understanding of how PPIn metabolism couples to individual physiological processes; ultimately, we aim to use this knowledge to develop strategies that modulate or restore PI(4,5)P2 regulation of individual functions that are aberrant in disease. Our goal in this application is to define three distinct mechanisms by which metabolism of PM PI(4,5)P2 or its signaling products couple to multiple physiological processes. In the first project, we leverage our recent discovery of a PM PI(4,5)P2 homeostatic mechanism to experimentally tune the lipid level in cells: this will allow us for the first time to determine the PI(4,5)P2 concentration-dependence of key PM functions. This will reveal which functions are most affected by pathogenic PI(4,5)P2 levels and thus likely drive disease phenotypes – a crucial first step in devising therapeutic interventions. In the second project, we will identify lipid transfer proteins (LTPs) that couple PPIn removal from membranes to their degradation by PPIn phosphatases located in other organelles. We will employ a synthetic biology approach in which LTPs deplete ectopic mitochondrial PPIn in live cells. Identifying LTPs coupled to different PPIn pools will reveal new targets to prevent PPIn accumulation in monogenic disease where phosphatase activity is lost. In the third project, we will define the distinct PI3K signaling landscapes driven by the two downstream lipid products of PI(4,5)P2: PIP3 and PI(3,4)P2. We will define the unique spatiotemporal and effector protein activation profiles of these lipids in live cells, using our unique molecular tools to precisely detect and chemogenetically manipulate the lipids in cell culture. Crucially, this will identify spatiotemporal and effector protein activation profiles that are unique to each lipid. This knowledge will be vital to eliminate on-target adverse effects of proven PI3K therapeutics. Collectively, at the conclusion of this funding cycle we expect to have defined fundamental principles by which specificity emerges from the coupling of PM PI(4,5)P2 signaling to individual PM functions in cells. This will be significant, because it will provide the conceptual framework for experimental and eventually therapeutic intervention in these isolated processes at the point of PI(4,5)P2 regulation.


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: 2026 ( Subtotal = $416,697 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	10	12/18/2025	NON-COMPETING CONTINUATION	$416,697
2026	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	9	12/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,697

Issue Date FY: 2025 ( Subtotal = $463,317 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	9	11/25/2024	NON-COMPETING CONTINUATION	$416,985
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	9	8/5/2025	NON-COMPETING CONTINUATION	$46,332
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	8	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $463,317

Issue Date FY: 2024 ( Subtotal = $463,627 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	8	6/10/2024	NON-COMPETING CONTINUATION	$46,363
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	8	12/7/2023	NON-COMPETING CONTINUATION	$417,264
														Subtotal = $463,627

Issue Date FY: 2023 ( Subtotal = $463,929 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	003	7	4/5/2023	NON-COMPETING CONTINUATION	$46,393
2023	2023	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	7	11/11/2022	NON-COMPETING CONTINUATION	$417,536
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	6	11/1/2022	COMPETING CONTINUATION	$125,139
2023	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	11/1/2022	NON-COMPETING CONTINUATION	-$125,139
														Subtotal = $463,929

Issue Date FY: 2022 ( Subtotal = $460,116 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	6	11/25/2021	COMPETING CONTINUATION	$460,116
2022	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	11/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $460,116

Issue Date FY: 2020 ( Subtotal = $466,483 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	5	7/16/2020	NON-COMPETING CONTINUATION	$391,250
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	6/5/2020	SUPPLEMENT FOR EXPANSION	$75,233
														Subtotal = $466,483

Issue Date FY: 2019 ( Subtotal = $391,251 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	7/16/2019	NON-COMPETING CONTINUATION	$391,251
														Subtotal = $391,251

Issue Date FY: 2018 ( Subtotal = $410,678 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	3	7/17/2018	NON-COMPETING CONTINUATION	$380,020
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	001	3	9/19/2018	SUPPLEMENT FOR EXPANSION	$30,658
														Subtotal = $410,678

Issue Date FY: 2017 ( Subtotal = $366,792 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	2	7/26/2017	NON-COMPETING CONTINUATION	$366,792
														Subtotal = $366,792

Issue Date FY: 2016 ( Subtotal = $352,774 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	7/29/2016	NEW	$352,774
														Subtotal = $352,774

Grand Total All Awards = $4,255,664

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Directing Membrane Function with Inositol Lipids in Health and Disease

Award Number: R35GM119412

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: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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