Molecular mechanisms of muscle thin-filament length regulation
Active Project Grant Awarded Last action
- Award ID
- F31HL184619
- Recipient
-
The Trustees Of The University Of Pennsylvania UEI GM1XX56LEP58
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 0% complete
- Place of performance
- Philadelphia, PA 19104, USA
Award details come from USAspending.gov.
Description
- Abstract
- The sarcomere, the basic contractile unit of striated muscles, is primarily composed of ACTIN and myosin polymers, known as the thin and thick filaments, respectively. The length of thin filaments is tightly regulated to ensure optimal overlap with thick filaments, which determines contraction strength and efficiency. Dysregulation of TFL is a major cause of cardiac and skeletal muscle diseases, most notably dilated cardiomyopathy (DCM) and nemaline myopathy (NM). At the core of thin filaments is filamentous ACTIN (F-ACTIN), a polymer with kinetically and structurally distinct barbed and pointed ends. In sarcomeres, the pointed end serves as the primary site for ACTIN subunit exchange. Despite the dynamic exchange of subunits at the pointed end, thin filaments display a uniform length across the sarcomere, suggesting that regulatory mechanisms mediated by ACTIN-binding proteins (ABPS) maintain this uniformity. However, these mechanisms remain poorly understood. The goal of this project is to elucidate the structural and functional mechanisms of pointed end thin-filament length (TFL) regulation by ABPS such as leiomodin (LMOD), SH3BGR, tropomodulin (TMOD), and tropomyosin (TPM). This will be achieved through the following aims: 1) determine the mechanism of LMOD-mediated thin filament elongation and 2) test the hypothesis that SH3BGR functions as a TFL regulator in sarcomeres. Aim 1 will be accomplished through the following subaims: a) determination of the structure of LMOD2-TPM and TMOD1-TPM at the pointed end of F-ACTIN using cryo-EM, B) assessment of the rate of LMOD-mediated elongation and its ability to replace TMOD at the pointed end using microfluidics-based tirf microscopy, and C) evaluate how disease-causing LMOD mutations linked to DCM and NM alter LMOD structure and function. Aim 2 will be achieved through the following subaims: a) test SH3BGR's pointed end capping activity using pyrene-ACTIN polymerization assays, B) determine cryo-EM structures of SH3BGR at the pointed end of F-ACTIN with and without TMOD and TPM, and C) elucidate SH3BGR localization in sarcomeres using immunofluorescence microscopy. Completion of these studies will provide a more comprehensive understanding of TFL regulation by LMOD and SH3BGR, the structure of the thin filament pointed end, and the mechanisms linking these proteins to myopathies resulting from TFL dysregulation.
Quick answers
Who received award F31HL184619?
F31HL184619 was awarded to The Trustees Of The University Of Pennsylvania by National Heart Lung and Blood Institute (National Institutes of Health) on December 1, 2026.
How much is award F31HL184619 worth?
$50,114 has been obligated on F31HL184619.
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