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Decoding mechanotransduction mechanisms of cell-surface receptors

Award Number: R35GM119483
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: 07/20/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Decoding mechanotransduction mechanisms of cell-surface receptors - PROJECT SUMMARY Recently, it has become apparent that mechanical cues in the cellular microenvironment drive cell migration, stem cell differentiation into distinct cell types and even how a surveilling T-cells is triggered by its correct antigen, solidifying tension-sensing as a key regulatory switch in cellular function. Not surprisingly, alteration of mechanical forces is an emerging factor in diseases like cancer, which makes intuitive sense given that diagnosis often involves detecting a lump that feels harder and stiffer than the surrounding tissue. Indeed, distinct and quantifiable “mechanical phenotypes” of normal and diseased cells/tissues have been measured. Underlying these cellular “mechanical phenotypes” characteristic of normal and diseased cellular microenvironments are mechanosensing proteins that convert sensed physical perturbations into biochemical signals in a process known as mechanotransduction. These signaling pathways are putative targets of emerging “mechano- therapeutic” strategies aimed to correct aberrant mechanical phenotypes. The overall vision of the Gordon lab is to innovate technology to identify the molecular players underlying disease-relevant mechanical-phenotypes, and dissect their tension-sensing mechanisms to cure disease. The greatest challenge to determining the molecular basis of force sensing is that the technology to measure picoNewton (pN) forces sensed by an individual protein in the context of the cell emerged only ten years ago, and is still under constant development. This has crippled identification of new mechanosensing proteins involved in a given cellular or disease process and also left a huge gap in testable hypotheses regarding how force alters the conformation of receptors to trigger a biological response. Our lab has established three major areas to tackle this problem that blend technology development and hypothesis driven questions. Program I. In combination with cellular imaging, we develop and use molecular tension sensors (MTS) to measure forces sensed by hypothesized mechanosensing proteins in the cellular context. We plan to combine MTS and CRISPR screens to identify mechanosensors involved in glioblastoma and T-cell migration. Program II. Second, we aim to test the hypothesis that proteolysis of receptors is a mechanism to convey mechanical stimuli. We will use structural biophysics to study newly identified Notch-like proteolytic switches and use CRISPR-tagging and mass spectrometry to study global receptor proteolysis in response to applied force. Program III. Finally, our lab has expanded into a third area- function and application of HUH-endonucleases as “HUH-tags” to covalently link proteins and DNA. We plan to engineer sequence specificity and RNA-binding of HUH-tags. We are poised to use HUH-tags to improve DNA- based MTS and to link mechanosensing-domains to DNA-nanostructures to coax proteins into mechanically activated conformations. The interleaving of new protein-DNA conjugation technology with hypothesis driven research drives creative and innovative approaches to important problems in biomedical science and medicine. 1


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 = $469,270 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	001	10	1/21/2026	SUPPLEMENT FOR EXPANSION	$88,685
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	10	1/16/2026	NON-COMPETING CONTINUATION	$380,585
														Subtotal = $469,270

Issue Date FY: 2025 ( Subtotal = $511,557 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	003	9	8/12/2025	NON-COMPETING CONTINUATION	$42,287
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	002	9	11/25/2024	SUPPLEMENT FOR EXPANSION	$88,685
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	9	11/20/2024	NON-COMPETING CONTINUATION	$380,585
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	8	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $511,557

Issue Date FY: 2024 ( Subtotal = $414,230 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	8	6/20/2024	NON-COMPETING CONTINUATION	$41,423
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	8	11/6/2023	NON-COMPETING CONTINUATION	$372,807
														Subtotal = $414,230

Issue Date FY: 2023 ( Subtotal = $414,230 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	7	2/21/2023	NON-COMPETING CONTINUATION	$41,423
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	7	12/6/2022	NON-COMPETING CONTINUATION	$372,807
														Subtotal = $414,230

Issue Date FY: 2022 ( Subtotal = $414,230 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	002	6	12/20/2021	COMPETING CONTINUATION	$414,230
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	004	6	6/15/2022	COMPETING CONTINUATION	$191,794
2022	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	003	5	6/15/2022	SUPPLEMENT FOR EXPANSION	-$191,794
2022	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	5	12/13/2021	SUPPLEMENT FOR EXPANSION	$0
2022	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	12/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $414,230

Issue Date FY: 2020 ( Subtotal = $827,693 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	5	6/24/2020	SUPPLEMENT FOR EXPANSION	$382,262
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	6/23/2020	NON-COMPETING CONTINUATION	$445,431
														Subtotal = $827,693

Issue Date FY: 2019 ( Subtotal = $445,431 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	4	6/21/2019	NON-COMPETING CONTINUATION	$371,432
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	4	7/10/2019	SUPPLEMENT FOR EXPANSION	$73,999
														Subtotal = $445,431

Issue Date FY: 2018 ( Subtotal = $371,432 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	7/16/2018	NON-COMPETING CONTINUATION	$371,432
														Subtotal = $371,432

Issue Date FY: 2017 ( Subtotal = $398,383 )
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	6/29/2017	NON-COMPETING CONTINUATION	$369,183
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	2	8/21/2017	SUPPLEMENT FOR EXPANSION	$29,200
														Subtotal = $398,383

Issue Date FY: 2016 ( Subtotal = $353,089 )
2016	2016	UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	7/20/2016	NEW	$353,089
														Subtotal = $353,089

Grand Total All Awards = $4,619,545

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Decoding mechanotransduction mechanisms of cell-surface receptors

Award Number: R35GM119483

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: 07/20/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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