Establishing and reversing the functional consequences of Titin truncation mutations

建立并逆转肌联蛋白截断突变的功能后果

基本信息

项目摘要

PROJECT SUMMARY/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.
项目总结/文摘

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance.
  • DOI:
    10.1172/jci175206
  • 发表时间:
    2024-01-16
  • 期刊:
  • 影响因子:
    15.9
  • 作者:
    Hinson, J. Travis;Campbell, Stuart G.
  • 通讯作者:
    Campbell, Stuart G.
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STUART G CAMPBELL其他文献

STUART G CAMPBELL的其他文献

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{{ truncateString('STUART G CAMPBELL', 18)}}的其他基金

Establishing and reversing the functional consequences of Titin truncation mutations
建立并逆转肌联蛋白截断突变的功能后果
  • 批准号:
    10510011
  • 财政年份:
    2022
  • 资助金额:
    $ 52.91万
  • 项目类别:
Computer modeling of myosin binding protein C and its effects on cardiac contraction
肌球蛋白结合蛋白 C 的计算机建模及其对心脏收缩的影响
  • 批准号:
    10371076
  • 财政年份:
    2019
  • 资助金额:
    $ 52.91万
  • 项目类别:
Computer modeling of myosin binding protein C and its effects on cardiac contraction
肌球蛋白结合蛋白 C 的计算机建模及其对心脏收缩的影响
  • 批准号:
    9903433
  • 财政年份:
    2019
  • 资助金额:
    $ 52.91万
  • 项目类别:
Revealing Pathomechanisms of Mutant TPM1 Through a Hybrid Computational-Experimental Approach
通过混合计算-实验方法揭示突变 TPM1 的病理机制
  • 批准号:
    10358783
  • 财政年份:
    2017
  • 资助金额:
    $ 52.91万
  • 项目类别:
Revealing Pathomechanisms of Mutant TPM1 Through a Hybrid Computational-Experimental Approach
通过混合计算-实验方法揭示突变 TPM1 的病理机制
  • 批准号:
    9398261
  • 财政年份:
    2017
  • 资助金额:
    $ 52.91万
  • 项目类别:
Revealing Pathomechanisms of Mutant TPM1 Through a Hybrid Computational-Experimental Approach
通过混合计算-实验方法揭示突变 TPM1 的病理机制
  • 批准号:
    9983135
  • 财政年份:
    2017
  • 资助金额:
    $ 52.91万
  • 项目类别:
Revealing Pathomechanisms of Mutant TPM1 Through a Hybrid Computational-Experimental Approach
通过混合计算-实验方法揭示突变 TPM1 的病理机制
  • 批准号:
    10221767
  • 财政年份:
    2017
  • 资助金额:
    $ 52.91万
  • 项目类别:
Computational Pipeline for Identification of Disease-Causing Variants in Genes of the Cardiac Sarcomere
用于鉴定心脏肌节基因致病变异的计算流程
  • 批准号:
    10736459
  • 财政年份:
    2017
  • 资助金额:
    $ 52.91万
  • 项目类别:
Engineered Tissue for Biomechanical Phenotyping of Cardiomyopathy Patients
用于心肌病患者生物力学表型分析的工程组织
  • 批准号:
    8974854
  • 财政年份:
    2014
  • 资助金额:
    $ 52.91万
  • 项目类别:

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