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Extracellular determinants of airway smooth muscle force: A new paradigm for sust

Award Number: R00HL122513
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/04/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Extracellular determinants of airway smooth muscle force: A new paradigm for sust - DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease that affects over 24 million people in the US and over 300 million people worldwide and its prevalence is rising. It is well recognized by now that chronic inflammation leads to an altered mechanical stiffness and composition of the airways referred to "airway remodeling". Further, changes in airway stiffness implies that, during tidal breathing, airway smooth muscle (ASM) cells will be subjected to an altered pattern of strains. This proposal addresses a critical question: Can the alterations in the mechanics of its extracellular environment drive the ASM cells into an altered baseline state such that upon agonist exposure, it can generate and sustain a force capable of amplified airway constriction? This proposal seeks to answer this question and identify the underlying mechanisms. Within the ASM, the contractile machinery of actin and myosin exists not only in the form of parallel arrays of contractile elements, but also as a very dense layer of actin close to cell membrane with non-muscle isoforms of myosin, referred to as the cortical actin (CA) network. Our central hypothesis is that alterations in the stiffness of the extracellula matrix (ECM) can cause the CA network to actively reorganize into unique configurations capable of sustaining exaggerated force generation by the ASM. This hypothesis derives from a computational model, that we developed, which shows that the ability of the ASM cells to maintain force for long periods of time can be explained by mechanical interactions between parallel array of actin myosin fibers and the CA network. The same model predicts that there are certain regimes of ECM stiffness that can cause the ASM generate very high forces when exposed to agonist. To experimentally verify these ideas, during the mentored phase of this proposal, I will gain training in primary human ASM cell culture, cellular traction force measurement, GFP labeling of actin and other cytoskeletal components and microscopy techniques for live cell imaging. This will be used to experimentally establish the effect of ECM stiffness on baseline and active force that an ASM can generate and determine a link between CA network structure and ASM force. Following this, I hope to transition into an independent investigator. During the R00 phase, I will examine the effect of stretch and deep breathing on cortical actin network geometry and how ASM cells can be driven into high or low force generating regimes using externally imposed strains and finally in aim 3, I will determine how these results scale to a multi-cellular ensemble of ASM cells with specific focus on understanding the effect of stretch and ECM stiffness on the strength of the coupling between ASM cells. Ultimately, this research may derive a new cellular and molecular based paradigm that explains how and why the ASM embedded in a remodeled airway can become hyperreactive and the role that dynamic forces play in sustaining or ablating this condition.


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: 2022 ( Subtotal = $0 )
2022	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	5	11/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $249,553 )
2019	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	001	5	7/12/2019	NON-COMPETING CONTINUATION	$249,000
2019	2017	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	10/26/2018	EXTENSION WITH OR WITHOUT FUNDS	$553
														Subtotal = $249,553

Issue Date FY: 2018 ( Subtotal = $249,000 )
2018	2018	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	4	6/21/2018	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2017 ( Subtotal = $249,000 )
2017	2017	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	5/17/2017	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $747,553

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Extracellular determinants of airway smooth muscle force: A new paradigm for sust

Award Number: R00HL122513

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/04/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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