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Unraveling cellular interactions as regulated by the mammalian secretory pathway with systems biology and algorithm development

Award Number: R35GM119850
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: 07/15/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Unraveling cellular interactions as regulated by the mammalian secretory pathway with systems biology and algorithm development - Contact PD/PI: Lewis, Nathan Enoch ABSTRACT The mammalian secretory pathway regulates a cell’s extracellular interactions by making most signals and receptors that moderate communication. Furthermore, it makes cell adhesion molecules and the extracellular matrix components. Indeed it makes most proteins needed for a cell to interact with its extracellular environment, which includes ~⅓ of their protein-coding genes in the human genome. The pathway has hundreds of machinery proteins used for synthesizing and trafficking secreted proteins, but each of these have their unique role in the process. However, for the ~8000 protein products of the secretory pathway, it remains unclear what machinery is needed for each one. To further complicate this, each tissue expresses its own subset of genes for the secretory pathway. Understanding the organization of the pathway and the interactions between the secretory pathway machinery and secreted protein products is of considerable importance since many diseases involve changes in the abundance of secreted and/or membrane proteins, and these are not always accompanied by changes in mRNA. That is, the secretory pathway itself is regulating changes in hormone secretion, managing ER stress, or amyloid formation. Thus, there is a fundamental need to understand (1) what the secretory pathway machinery does, (2) which secreted and membrane proteins rely upon it, (3) how the hundreds of machinery proteins work together, and (4) what regulates their functions. All of these items require systems-level experiments, tools, and analyses to fully understand. Here we are developing such resources for the community to answer fundamental questions. In this work, we are mapping out all of the secretory pathway machinery and detailing their functions. We describe their functions mathematically, and build computational models to account for their concerted functions, even for individual tissues and cell types. Furthermore we are developing software and algorithms to help analyze the models and use them to diagnose the molecular bases underlying secretory disorders. We are further developing and deploying experimental techniques to more fully identify all of the secretory machinery proteins needed to facilitate the production of each specific secreted or membrane protein, and will use those techniques to identify these interactions for liver-secreted proteins. Finally, we are using genomics and systems biology techniques to unravel the regulatory mechanisms controlling the tissue-specific expression of the secretory pathway. Through this, valuable resources will be developed and shared with the community to make it easier to study the secretory pathway as a biomolecular system. Project Summary/Abstract Page 6


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: 2027 ( Subtotal = $0 )
2027	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	10	10/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = -$39,654 )
2026	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	003	11	8/31/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$350,319
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	10	8/21/2026	NON-COMPETING CONTINUATION	-$389,973
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	10	6/30/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	10	8/24/2026	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = -$39,654

Issue Date FY: 2025 ( Subtotal = $441,394 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	10	9/18/2025	SUPPLEMENT FOR EXPANSION	$6,894
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	10	9/17/2025	NON-COMPETING CONTINUATION	$434,500
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	11/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $441,394

Issue Date FY: 2024 ( Subtotal = $517,234 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	9	6/24/2024	SUPPLEMENT FOR EXPANSION	$82,734
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	9	6/21/2024	NON-COMPETING CONTINUATION	$434,500
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	12/19/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $517,234

Issue Date FY: 2023 ( Subtotal = $510,340 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	8	9/22/2023	SUPPLEMENT FOR EXPANSION	$75,840
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	9/21/2023	NON-COMPETING CONTINUATION	$434,500
														Subtotal = $510,340

Issue Date FY: 2022 ( Subtotal = $434,500 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	7	6/28/2022	NON-COMPETING CONTINUATION	$434,500
														Subtotal = $434,500

Issue Date FY: 2021 ( Subtotal = $460,962 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	5/28/2021	COMPETING CONTINUATION	$460,962
2021	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	9/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $460,962

Issue Date FY: 2020 ( Subtotal = $387,500 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	7/30/2020	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2019 ( Subtotal = $387,500 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	6/21/2019	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2018 ( Subtotal = $387,500 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	6/21/2018	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2017 ( Subtotal = $387,500 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	6/16/2017	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2016 ( Subtotal = $387,500 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	7/14/2016	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $4,262,276

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Unraveling cellular interactions as regulated by the mammalian secretory pathway with systems biology and algorithm development

Award Number: R35GM119850

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: 07/15/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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