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The Molecular Basis for Integrin-Mediated Bidirectional Signaling

Award Number: R35GM147414
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: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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The Molecular Basis for Integrin-Mediated Bidirectional Signaling - Leukocytes are essential immune components protecting the body against foreign invaders. Adhesion, migration, extravasation, and cell-cell communication are mediated though the bidirectional signaling of β2 integrins, which are integral membrane proteins found on the leukocyte surface. Due to their complex and multifunctional roles, dysregulation of β2 integrins is linked to autoimmune, cardiac and pulmonary pathologies as well as infectious diseases and several cancers. Although integrins are prime therapeutic targets, drug development has been hindered due to unanticipated side effects that arise from large gaps in our understanding of the mechanisms that drive specificity and integrin activation. I will decipher the molecular basis for β2 integrin activation, ligand recognition, and bidirectional signaling using an integrative approach. I'll build on my expertise in cryoEM method development to capture high- resolution conformational snapshots of isolated β2 integrin and ligand-bound complexes to reveal the dynamic structural rearrangements associated with signal transduction and identify key residues mediating ligand specificity. Using cell-surface expressed integrins, I'll assess the functional consequences of mutating these residues on binding of ligands and conformation- specific antibodies and on adhesion, phagocytosis, and cell motility. To gain broad insight into integrin allostery in a near-native context, I'll develop a membrane mimetic system using next- generation styrene maleic acid copolymers. Membrane lipids influence integrin activation and ligand binding and are key to forming stable complexes. These polymers will afford a stream- lined method to extract and purify nanodiscs embedded with pre- formed integrin-ligand complexes in their native environment. I will use this system to study integrin in complex with talin, the central integrin- activator protein that binds a conserved motif on the cytoplasmic region on integrin. This will reveal in molecular detail how integrins are activated to relay signals allosterically across the plasma membrane and define a molecular basis for bidirectional signaling as well as provide a framework for designing biochemical, biophysical, and mechano- sensitive experiments to study larger complexes and gain comprehensive insight into integrin function. Ultimately, this work will provide a structural blueprint for the rational design of therapeutics for autoimmune diseases, which is a long-term goal of the lab.


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: 2025 ( Subtotal = $440,000 )
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	4	6/11/2025	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2024 ( Subtotal = $440,000 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	3	7/1/2024	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2023 ( Subtotal = $440,000 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	2	6/22/2023	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2022 ( Subtotal = $440,000 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Biomedical Research and Research Training	000	1	9/1/2022	NEW	$440,000
														Subtotal = $440,000

Grand Total All Awards = $1,760,000

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The Molecular Basis for Integrin-Mediated Bidirectional Signaling

Award Number: R35GM147414

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: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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