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Decoding kindlin-3 signaling in platelets and neutrophils

Award Number: R35HL183465
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2032

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Decoding kindlin-3 signaling in platelets and neutrophils - PROJECT SUMMARY The studies proposed in this application reflect the Principal Investigator’s long-standing commitment to unraveling the regulatory role of kindlin-3 signaling in thrombosis and inflammation. These investigations aim to address critical conceptual gaps relevant to the NHLBI’s mission, as thrombosis and inflammation are interrelated pathophysiological processes contributing to numerous diseases, including cardiovascular disease, acute and chronic lung injury, venous thromboembolism, autoimmune disorders, and sepsis. Central to these processes are platelets and neutrophils, whose dysregulation can lead to severe complications, such as excessive clotting or tissue damage. Our research focuses on elucidating the molecular mechanisms by which kindlin-3, a critical signaling adaptor expressed in cells of hematopoietic origin, regulates platelet activation during thrombosis and neutrophil activity during inflammation. Kindlin-3 is essential for supporting integrin αIIbβ3 activation in platelets, yet its precise role in regulating integrin bidirectional signaling remains poorly understood. Based on our novel discovery that kindlin-3 interacts with myosin in platelets, we hypothesize that the crosstalk between kindlin-3 and the myosin complex facilitates integrin αIIbβ3 activation during inside-out signaling and promotes myosin activation during outside-in signaling. To test this hypothesis, we will investigate the structural basis of the kindlin-3-myosin complex and assess the functional impact on platelet activation and activity using designed kindlin-3 knock-in mouse models. Kindlin-3 exhibits dual roles in neutrophils, acting as a pro-inflammatory and anti-inflammatory regulator. While kindlin-3 promotes β2-integrin- mediated neutrophil recruitment, our recent findings indicate that it also suppresses reactive oxygen species (ROS) production and neutrophil extracellular trap (NET) release in an integrin-independent manner. We propose that kindlin-3 levels in neutrophils are dynamically regulated across different stages of inflammation to balance these opposing functions. Specifically, we aim to elucidate how kindlin-3 is downregulated in extravasated neutrophils at the late stage of inflammation and the mechanism by which it modulates ROS and NET signaling in cellular and mouse models. Collectively, this program will leverage cutting-edge technology by integrating structural and cellular biology with ex vivo and in vivo models to decode the critical role of kindlin-3 signaling in platelets and neutrophils. These insights will lay the groundwork for advances in understanding and treating blood and vascular disorders, aligning well with the mission of the NHLBI.


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 = $1,069,072 )
2026	2026	VERSITI BLOOD HEALTH, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	1	3/10/2026	NEW	$1,069,072
														Subtotal = $1,069,072

Grand Total All Awards = $1,069,072

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Decoding kindlin-3 signaling in platelets and neutrophils

Award Number: R35HL183465

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2032

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