Thick and Thin Filament Dysfunction in Obese Heart Failure with Preserved Ejection Fraction

射血分数保留的肥胖性心力衰竭的粗细丝功能障碍

基本信息

  • 批准号:
    10678204
  • 负责人:
  • 金额:
    $ 5.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Heart Failure with Preserved Ejection (HFpEF) is one of the largest unmet needs of all cardiovascular disease. Although it now is the most common form of heart failure, to date, it has little to no specific effective therapy. An obesity pandemic has now changed its phenotype, with obesity and metabolic syndrome now significant drivers of the disease. We recently reported that an obese-HFpEF phenotype exhibits striking depression of right ventricular myocyte tension generation at higher (contraction-related) levels of calcium. Critically, the mechanism by which this occurs is unknown. Myocyte tension is regulated by both the thick filament, consisting of myosin, and the thin filament, consisting of actin, tropomyosin, and cardiac troponins. In the thick filament, approximately half of all myosin heads are in a conformation known as the super-relaxed (SRX) state, and the proportion of myosin in this state is an important regulator of tension. The thin filament regulates tension by altering calcium sensitivity, and one regulator is phosphorylation of cardiac troponin I (cTnI). In exciting new preliminary data, I find that thick filament structure and phosphorylation of myofilament proteins are altered in obese-HFpEF. This proposal derives from these data and aims to elucidate how obesity alters the thick and thin filament in human HFpEF. In Aim 1, I will test the hypothesis that structural inactivation of the thick filament in obese-HFpEF results from an excess of SRX myosin. To assess thick filament structure, I use small angle x-ray diffraction, a technique that leverages the ordered structure of cardiac muscle to quantify distances between sarcomere proteins. This technique is performed at the synchrotron at Argonne National Laboratory, one of few locations globally that can perform the assay, and this proposal describes the first application of this technique to endomyocardial biopsies from human HFpEF patients. While informative, X-ray diffraction on its own cannot prove the presence of excess SRX myosin. For this, I will measure the myosin ATP turnover from single cardiomyocytes from HFpEF patients. I will then explore whether obesity is a driver of excess SRX myosin by measuring both assays in HFpEF patients with both obesity and hypertension/hypertrophy. In Aim 2, I explore the mechanism underlying how hyperphosphorylation alters calcium activated tension. My preliminary data finds that the exposure to enzymatically active protein phosphatase 2A (PP2A) partially reverses the deficit observed in calcium activated tension in obese HFpEF, but the mechanism is unknown. I will test if this is from thick filament activation by measuring x-ray diffraction patterns and myosin ATP turnover after PP2A exposure. I also test if this results from thin filament hyperphosphorylation, specifically at cTnI, in HFpEF. We have identified a novel threonine 181 residue of cTnI to be hyperphosphorylated in HFpEF, but its function is unknown. Phospho-null/mimetic transgenic cTnI Thr181 will be swapped into skinned myocytes from HFpEF patients, and myocyte tension measured. These studies will advance our understanding of the thick and thin filament in HFpEF and could pave the way for new therapies with small molecule sarcomere enhancers that target these mechanisms.
项目摘要 射血功能保留性心力衰竭(HFpEF)是所有心血管疾病中最大的未满足需求之一。 尽管它现在是心力衰竭最常见的形式,但迄今为止,它几乎没有具体有效的治疗方法。一个 肥胖症的流行现在已经改变了它的表型,肥胖症和代谢综合征现在是重要的驱动因素 的疾病。我们最近报道了一种肥胖型HFpEF表型表现出显著的右心室收缩抑制, 心室肌细胞在较高的(收缩相关的)钙水平下产生张力。关键是, 这种情况发生的原因是未知的。肌细胞张力由肌球蛋白组成的粗肌丝, 以及由肌动蛋白、原肌球蛋白和心肌肌钙蛋白组成的细丝。在粗丝中,大约 所有肌球蛋白头部的一半处于被称为超松弛(SRX)状态的构象,并且 这种状态下的肌球蛋白是张力的重要调节剂。细丝通过改变钙来调节张力 一种调节因子是心肌肌钙蛋白I(cTnI)的磷酸化。在令人兴奋的新的初步数据,我 发现肥胖HFpEF中的粗丝结构和肌丝蛋白的磷酸化改变。这 一项提案源于这些数据,旨在阐明肥胖如何改变人类的粗丝和细丝。 HFpEF。在目标1中,我将检验肥胖HFpEF中粗纤维的结构失活导致 SRX肌球蛋白过量所致为了评估粗灯丝结构,我使用小角度X射线衍射, 利用心肌的有序结构来量化肌节蛋白之间的距离。这 这项技术是在阿贡国家实验室的同步加速器上进行的,阿贡国家实验室是全球少数几个可以 进行测定,该建议描述了该技术首次应用于子宫内膜活检 来自人类HFpEF患者。虽然信息丰富,但X射线衍射本身不能证明存在过量的 SRX肌球蛋白。为此,我将测量HFpEF患者单个心肌细胞的肌球蛋白ATP周转率。 然后,我将通过测量HFpEF患者的两种检测方法来探索肥胖是否是过量SRX肌球蛋白的驱动因素 患有肥胖症和高血压/肥大症。在目标2中,我探讨了 过度磷酸化改变钙激活张力。我的初步数据显示, 酶活性蛋白磷酸酶2A(PP 2A)部分逆转了在钙激活的细胞中观察到的缺陷。 肥胖HFpEF的张力,但机制尚不清楚。我将测试这是否是由粗灯丝激活引起的, 测量PP 2A暴露后的X射线衍射图和肌球蛋白ATP周转率。我还测试了这是否是由于 HFpEF中细纤维过度磷酸化,特别是cTnI。我们已经鉴定了一种新的苏氨酸181 在HFpEF中,cTnI残基被过度磷酸化,但其功能尚不清楚。磷酸化无效/模拟 将转基因cTnI Thr 181交换到来自HFpEF患者的皮肤肌细胞中, 测定了这些研究将促进我们对HFpEF中粗丝和细丝的理解, 新疗法的方式与小分子肌节增强剂靶向这些机制。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Vivek Pinakin Jani其他文献

Vivek Pinakin Jani的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 5.27万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了