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Signaling To and From the Vascular/Endothelial Compartment and Progression of HCM Linked to Sarcomere Mutations

Award Number: R01HL158634
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Signaling To and From the Vascular/Endothelial Compartment and Progression of HCM Linked to Sarcomere Mutations - Project Summary/Abstract Hypertrophic cardiomyopathy (HCM) is a common familial cardiovascular disorder viewed as a genetic disease of the sarcomere, since most mutations occur in genes that encode sarcomere/cytoskeletal proteins. Despite decades of basic and clinical research, there are critical gaps in our knowledge concerning how defective biophysical signals in the myocyte influence the function of other cellular compartments of the heart during the clinical course of this disorder. We have reported that early interventions aimed at normalizing myofilament properties only partially prevent HCM progression. Moreover, removal of the triggering mutation does not always reverse progression. In experiments proposed here, we test the overall hypothesis that critical, but treatable, maladaptive modifications in the vascular/endothelial compartment occur early and in parallel with changes in myofilament properties in the progression of HCM linked to thin filament mutations triggering different biophysical and biochemical signals. Preliminary data strongly support a role for and a need to investigate vascular remodeling and endothelial dysfunction that exacerbate symptomatic HCM. Novel data support our focus on HIPPO/YAP/TAZ signaling with emphasis on protective effects of sphingsine-1-phosphate receptor (S1PR) signaling, which is common to the endothelium (EC) and myocytes (CM). Our aims are as follows: Aim 1. Determine the decline in coronary function, changes in vascular remodeling and mechano- sensing in HCM linked to mutationsTnT-R92Q and Tm-E180G with different signaling in progression to HCM. Aim 2. Establish whether restoration of the endothelial HIPPO pathway is sufficient to impede HCM progression. Evidence provided here for a role of EC HIPPO/YAP/TAZ signaling in HCM progression demands an investigation of the consequences of its regulation, and whether therapeutic interventions modify HIPPO signaling. Aim 3. Evaluate the microenvironmental signals responsible for HIPPO pathway dysregulation and co-translation expression of activated YAP/TAZ protective mediators in HCM. Our approach includes determination of the time course of changes in coronary flow velocity, vascular/endothelial histology, and mechano-sensing through key components of the HIPPO pathway, with changes in cardiac function and the myofilaments Ca2+-response during HCM progression. We will treat mouse models early in HCM progression with S1PR agonists, and small molecule inhibitors to normalize myofilament Ca2+ sensitivity and tension to examine whether they restore EC HIPPO pathway and angiogenic signaling. We will identity EC and CM specific disease signaling networks and determine whether HCM leads to impaired S1P export and paracrine function, by enriching and probing the functional co-translatome in the RiboTag reporter mice crossed with HCM mutations. Accomplishing our aims will provide discovery of targets for effective and individualized therapies for HCM.


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 = $716,102 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	4	2/20/2025	NON-COMPETING CONTINUATION	$716,102
														Subtotal = $716,102

Issue Date FY: 2024 ( Subtotal = $782,105 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	3	3/13/2024	NON-COMPETING CONTINUATION	$718,260
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	3	6/22/2024	NON-COMPETING CONTINUATION	$63,845
														Subtotal = $782,105

Issue Date FY: 2023 ( Subtotal = $779,861 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	2	3/20/2023	NON-COMPETING CONTINUATION	$779,861
														Subtotal = $779,861

Issue Date FY: 2022 ( Subtotal = $708,159 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	1	3/30/2022	NEW	$708,159
														Subtotal = $708,159

Grand Total All Awards = $2,986,227

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Signaling To and From the Vascular/Endothelial Compartment and Progression of HCM Linked to Sarcomere Mutations

Award Number: R01HL158634

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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