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Structural mechanism of integrin-mediated TGF-b activation

Award Number: R01HL134183
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Structural mechanism of integrin-mediated TGF-b activation - Summary/Abstract: The multifunctional cytokine TGF-β is a central mediator of the chronic inflammatory and fibrotic pathologic processes that leads to lung and airway fibrosis. Our long-term goals for this project are to acquire a deeper understanding of how TGF-β function is regulated, and to leverage that understanding to develop new strategies and treatments for fibrosing lung disease. There is an urgent need for effective therapies to treat chronic fibrosing and inflammatory diseases of the lung. Clinical trials targeting TGF-β itself or its receptors has faced challenges, most notably, toxicities. More understanding of how TGF-β functions is clearly needed to develop better and more specific methods to more effectively target the pathologic effects of TGF-β. Since TGF-β is always produced in an inactive form that must be activation to function, methods targeting its activation may more specifically target the local effects of TGF-β thus avoiding systemic toxicities. TGF-β is activated by binding to several integrins. What exactly happens biologically after these integrins bind to TGF-β remains largely speculative. Because of this lack of biologic understanding it has long been assumed that TGF-β must be released from LAP so that free TGF-β can operate as a paracrine factor and diffuse and bind its receptors on target cells. Based on our recent structural data obtained using single particle electron cryomicroscopy (cryo-EM), we have developed a new hypothesis where integrins can bind to L-TGF-β on cells presenting the L-TGF-β on their cell surface and induce autocrine signaling without release and diffusion of TGF-β. We have recently verified that such an autocrine mechanism is sufficient to maintain the essential functions of TGF-β1 in mice, and that paracrine TGF-β1 signaling is dispensable. We now have structural and cell-based data that provides a new hypothesis for TGF-β1 activation: The inherent disorder (entropy) present in specific domains of TGF-β1 and integrin αvβ8 is redistributed upon binding of L-TGF-β1 to αvβ8 which is sufficient to cause exposure of mature TGF-β1 to its receptors. Here in three aims, we address three critical questions concerning this new model of L-TGF-β activation. (1) Can entropy redistribution of the L-TGF-β/αvβ8 complex be predicted by structural methods, and if so can it be biochemically and therapeutically manipulated? (2) How does a native membrane environment affect entropy redistribution of the L-TGF-β/αvβ8 complex? (3) Can the entropy redistribution hypothesis be applied to other integrins and can it be harnessed to be therapeutically useful to treat lung fibrosis? To answer these questions, we will establish and employ state-of- the-art techniques including cryo-EM coupled to orthogonal spectroscopic, and analytical techniques to more quantitatively assess protein thermodynamics, protein engineering, recombinant antibodies to affect local protein conformational dynamics and finally testing of those antibodies in lung fibrosis models in vivo. Together, these studies will improve mechanistic understanding of TGF-β activation and therapeutic targeting strategies to inhibit it.


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 = $816,051 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	9	5/14/2026	COMPETING CONTINUATION	$816,051
														Subtotal = $816,051

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	8	8/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $737,918 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	8	5/10/2023	NON-COMPETING CONTINUATION	$737,918
														Subtotal = $737,918

Issue Date FY: 2022 ( Subtotal = $737,918 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	7	4/29/2022	NON-COMPETING CONTINUATION	$737,918
														Subtotal = $737,918

Issue Date FY: 2021 ( Subtotal = $737,918 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	002	6	5/19/2021	NON-COMPETING CONTINUATION	$737,918
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	5	2/26/2021	COMPETING CONTINUATION	$44,124
2021	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	4	2/26/2021	NON-COMPETING CONTINUATION	-$44,124
														Subtotal = $737,918

Issue Date FY: 2020 ( Subtotal = $737,537 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	5	5/26/2020	COMPETING CONTINUATION	$737,537
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	4	5/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $737,537

Issue Date FY: 2019 ( Subtotal = $536,508 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	4	4/26/2019	NON-COMPETING CONTINUATION	$536,508
														Subtotal = $536,508

Issue Date FY: 2018 ( Subtotal = $536,508 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	3	4/13/2018	NON-COMPETING CONTINUATION	$536,508
														Subtotal = $536,508

Issue Date FY: 2017 ( Subtotal = $536,454 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	2	4/25/2017	NON-COMPETING CONTINUATION	$536,454
														Subtotal = $536,454

Issue Date FY: 2016 ( Subtotal = $536,020 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	1	7/4/2016	NEW	$536,020
														Subtotal = $536,020

Grand Total All Awards = $5,912,832

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Structural mechanism of integrin-mediated TGF-b activation

Award Number: R01HL134183

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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