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Cooperative Modulation of Piezo Channels

Award Number: R01HL179692
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Cooperative Modulation of Piezo Channels - SUMMARY Mechanosensitive PIEZO channels sense various forms of mechanical deformations within cells and tissues. In the cardiovascular system, these proteins are essential to detect blood and lymph flow, blood pressure, and cardiac contractions. PIEZO1 dysfunctions are associated with various cardiovascular pathologies including hypertension, xerocytosis, dilated cardiomyopathy, and lymphedema. Understanding how these proteins activate in the native cellular context is needed to better understand how mechanical sensations are perceived, and how these diseases emerge and could be treated more effectively. At the molecular level, PIEZO channels possess a non- planar bowl-like structure that creates a curvature in the surrounding membrane, known as “PIEZO membrane footprint”. Mechanical forces that stretch or flatten the PIEZO footprint promote a flattened channel conformation thought to be associated with an open channel. When multiple channels diffuse at a high density in a membrane at rest, their large footprints are predicted to frequently collide. This proposal tests the hypothesis that such collisions remodel adjacent PIEZO footprints, promoting cooperative interactions that favor channel clustering and modulation of channel activity. In Aim1, we use multi-scale molecular dynamics simulations to study the energetics and dynamics of footprint-footprint interactions in large membranes. In Aim2, we use high-speed single molecule Ca2+ imaging to map the mobility and activity of endogenous PIEZO1 channels expressed at the surface of endothelial cells derived from human induced pluripotent stem cells. This will allow us to examine cooperativity between neighboring channels under physiological conditions. In Aim3, we use high-resolution patch clamp electrophysiology to precisely quantify cooperativity by comparing the distributions of multi-channel open probabilities to binomial distributions expected for independent channels. If successful, this project will establish PIEZO1 cooperativity as a potential mechanism to contextually regulate mechanotransduction signaling, enhancing our understanding of its role in cardiovascular health and disease.


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 = $613,305 )
2026	2026	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	5/20/2026	NON-COMPETING CONTINUATION	$613,305
														Subtotal = $613,305

Issue Date FY: 2025 ( Subtotal = $636,822 )
2025	2025	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	7/21/2025	NEW	$636,822
														Subtotal = $636,822

Grand Total All Awards = $1,250,127

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Cooperative Modulation of Piezo Channels

Award Number: R01HL179692

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/21/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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