Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

The interaction of myosin and the thin filament: how sarcomeric mutations cause allosteric dysfunction and their connections to genetic cardiomyopathies

Award Number: R01HL182883
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

Group Awards By:

View Award Description

The interaction of myosin and the thin filament: how sarcomeric mutations cause allosteric dysfunction and their connections to genetic cardiomyopathies - Project Summary: The studies proposed in this application significantly extends our program devoted to developing an atomistic picture of the function of the sarcomere both in health and in the presence of mutations that cause Hypertrophic Cardiomyopathy (HCM). In the last few years, a cryo-EM structure of the cardiac thin filament (CTF) was published that both validated our earlier model and provided critical refinements. As important as this structure was, it was uninformative in two basic areas. First, there are multiple regions of the CTF containing highly mobile regions that are known to be critical to proper cardiac muscle regulation, but that cannot be resolved in any standard structural technique. To address this, we have developed a coupled Time-Resolved FRET computation-based method, and we will extend its application to the highly mobile, unstructured N-Term of cTnT and its potential interactions with the C-terminus of cTnI of the adjacent thin filament unit. This will allow us to investigate a previously unexplored question – do successive CTF units dynamically interact to modulate function via interactions between highly mobile regions in the N- terminal of cTnT and the C-terminal of cTnI. The current three-state model does not address this interaction, but preliminary evidence suggests it exists. Second, no purely static structure can fully inform on a process that is inherently dynamic in both function and transmission of mutation effects. We will thus study how mutational effects in the CTF are allosterically transmitted to alter function in regions remote from the primary location. We will study how myosin mutations can affect the function of the CTF and equally how CTF mutations affect bound myosin. In this proposal we will expand both our experimental and computational studies from myosin S1 to HMM and to expand our work to higher levels of biological complexity through the interaction of myosin and the CTF in the model and via loaded myofibril kinetics. While myofibrils are too complex to model atomistically, we will develop connections between atomistic level predictions and these experiments including the potential role of phosphorylation events. Two Specific Aims will be pursued: Aim 1 will use TR-FRET studies in concert with our most recent version of the CTF model to, for the first time, map the N-terminal region of cTnT and elucidate its interactions with the C-terminus of cTnI and thus allow us to explore the potential interactions between 2 contiguous thin filament units and provide novel mechanistic insights into the effects of known cTnI HCM mutations in this complex region. In Aim 2 we will study how mutations in myosin and the cardiac thin filament affect each other at each stage of the cross-bridge cycle. The end goal of this program is to develop a fully atomistic treatment of the structure, dynamics, and function of this complex molecular machine and to connect our atomistic level studies to measurements at higher levels of biological complexity. The overall motivation is to provide the community with the most complete models and tools for studying and targeting the cardiac sarcomere.


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 = $650,419 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	1	7/10/2026	NEW	$650,419
														Subtotal = $650,419

Grand Total All Awards = $650,419

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The interaction of myosin and the thin filament: how sarcomeric mutations cause allosteric dysfunction and their connections to genetic cardiomyopathies

Award Number: R01HL182883

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer