R01HL158634

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 sphingosine-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 mutations TnT-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 identify 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.

University Of Illinois

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Chicago, Illinois 60612 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 333% from $708,159 to $3,065,794.