Wednesday, May 8, 2024 5/8/2024

Research Supplements to Promote Diversity in Health-Related Research Mechanisms of APP ectodomain function

Award Number: R35GM142726
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 Cell membrane proteins regulate a multitude of cellular processes that are vital for organismal health. The extracellular domain is critical for ligand binding and signal transduction of the full-length receptor. In addition, approximately 2% of cell surface proteins undergo ectodomain shedding to release their extracellular domain. Ectodomain shedding may terminate the function of the full-length receptor and/or lead to the generation of either a soluble decoy receptor or an active ligand. The Amyloid Precursor Protein (APP), a type 1 membrane protein central to the etiology of Alzheimer’s disease, is one such cell surface protein that undergoes ectodomain shedding to generate various soluble APP (sAPP) fragments. Despite the known effects of the APP ectodomain on cellular and cognitive functions and the potential applications to disease, the precise molecular mechanisms mediating the function of APP ectodomain remains largely enigmatic due to the focus of the field on the Amyloid- ß region of APP. Thus, the goal of the lab is to elucidate the normal physiological functions of the extracellular domain of the Amyloid Precursor Protein. Our approaches are designed to address the mechanistic gaps in knowledge by leveraging our recent discovery that sAPP functions as a ligand for the GABA type B Receptor (GABABR) and our recent identification of Phosphoglycerate Mutase Family Member 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, as a novel candidate interactor of the APP ectodomain. One line of research will elucidate the cellular responses of non-neuronal cells to sAPP and GABA B Receptor modulation, identify signaling pathways downstream of the sAPP and GABA B Receptor interaction, and determine mechanisms involved in the positive regulation of GABA B Receptor signaling by sAPP. A second line of research will investigate the cellular conditions and subcellular compartments in which APP and PGAM5 come into contact, the molecular basis of the APP and PGAM5 interaction (i.e. binding affinities, critical binding domains), and the consequences of PGAM5 on APP phosphorylation and proteolytic processing. The work in these studies will generate fundamental knowledge of the molecular mechanisms underlying the protein-protein interactions of the APP ectodomain and the cellular consequences of these interactions across different cell types.


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 = $50,836 )
2024	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	002	4	3/28/2024	SUPPLEMENT FOR EXPANSION	$17,901
2024	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	001	4	1/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$220,211
2024	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	000	3	1/29/2024	NON-COMPETING CONTINUATION	-$187,276
														Subtotal = $50,836

Issue Date FY: 2023 ( Subtotal = $362,500 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	000	3	6/8/2023	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2022 ( Subtotal = $362,500 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	000	2	6/13/2022	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2021 ( Subtotal = $362,500 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	000	1	8/30/2021	NEW	$362,500
														Subtotal = $362,500

Grand Total All Awards = $1,138,336

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Research Supplements to Promote Diversity in Health-Related Research Mechanisms of APP ectodomain function

Award Number: R35GM142726

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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