Establishing and reversing the functional consequences of titin truncation mutations

Active Project Grant Awarded Last action

Award ID
R01HL165220
Recipient
Awarding agency
Obligated
$4,322,414

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 86% complete
Originally
Funding
  • $3,756,312.00 Federal
  • $566,102.00 Non-federal
Place of performance
Farmington, CT 06032, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Cardiomyopathies occur in ~1:200 individuals and are commonly caused by inheritance of variants in genes that encode proteins that regulate the sarcomere, the force-producing organelle of heart cells. Due to an incomplete understanding of variant pathogenicity and cardiomyopathy pathogenesis, physicians are currently limited in their ability to provide diagnoses, prognoses, and therapeutic options for cardiomyopathy patients. Variants in the TTN gene, which encodes the sarcomere protein titin, are the most frequently identified genetic lesion in dilated cardiomyopathy (DCM), which is characterized by heart chamber dilation, reduced contractile function, risk of sudden death, and progressive heart failure. The most frequent type of TTN variant identified in DCM is a truncation mutation that would be predicted to shorten TTN protein length and to reduce TTN protein quantities. Significantly, truncation variants localized to distal TTN structural domains are more pathogenic than those localized to proximal structural domains, but the mechanistic basis for this relationship is uncertain. IT remains incompletely understood how TTN truncation variants cause DCM generally, which is compounded by our lack of understanding of the 'length dependence' of TTN variant pathogenicity. These knowledge gaps limit disease prognostication, biomarker identification, and therapeutic development for DCM patients. The central goal of our study is to define how disruptions in TTN length and dosage by TTN variants cause DCM, and exploit this knowledge to develop DCM therapeutics for TTN variant carriers. We hypothesize that healthy cardiac contractile function and structure depends on the regulation of TTN length and dosage, and that varying pathogenicity of TTN truncation can be explained by distinct structural and functional consequences associated with the specific site of truncation. In aim 1, we will determine the functional consequences of TTN truncations across structural domains by harnessing 3-dimensional heart tissue models composed of human cardiomyocytes differentiated from induced pluripotent stem cells in which variants have been introduced by crispr-mediated genome editing. We will interrogate these models for tissue mechanical phenotypes (such as passive tension and frank-starling behavior), TTN protein length and levels (using specialized methods), proteostasis stress pathway responses (using immunoblotting), and mechanotransduction signaling and alternative splicing (using expression analysis and transcriptomics, respectively). In aim 2, we will restore TTN protein levels using the recently developed method of crispr activation applied to DCM engineered heart tissue models for both evaluating the function of TTN isoforms generally and as a DCM proof-of-concept therapeutic. Through these aims, we will gain critical new insights into the pathophysiology of DCM-associated TTN truncation variants, uncover features to explain the variable pathogenicity identified in DCM patients, and develop a therapeutic to target TTN directly. We anticipate this new knowledge will improve physicians' capacity to diagnose, prognose, and treat patients with DCM due to TTN variants.

Transactions

Action Federal Non-federal Date
Amendment $0 $0
Amendment $529,054 $0
Amendment $518,473 $0
Amendment $518,473 $0
Amendment $529,054 $0
Amendment $529,054 $0
Amendment $566,102 $0
Original award $566,102 $566,102

Subawards

Subrecipient Amount Awarded
Jackson Laboratory The purpose of the subaward amendment is to extend the period of performance to 6.30.2027 and to decrease the subaward in the amount of $3,844. The scope of… -$3,844
Jackson Laboratory All experimental work will be done for this proposal at JAX-GM. This includes the generation of iPSc models harboring DCM-associated TTN mutations, VAGE protein… $216,003
Yale Univ The goal of this project is to relate different TTN gene mutations to their detailed cardiac muscle phenotypes. iPSC lines genetically manipulated to contain… $150,658
Jackson Laboratory All experimental work will be done for this proposal in the Hinson lab will be done at JAX-GM. -This includes the generation of iPSc models harboring… $295,344
Yale Univ Mutations to the gene TTN, which encodes the muscle protein titin, are an important cause of heart failure. Because of its enormous size and potential for… $150,658

Quick answers

Who received award R01HL165220?

R01HL165220 was awarded to University Of Connecticut Health Center by National Heart Lung and Blood Institute (National Institutes of Health) on July 1, 2022.

How much is award R01HL165220 worth?

$4,322,414 has been obligated on R01HL165220: $3,756,312 in federal funding and $566,102 in non-federal funding.

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