The role of obscurin and Obsl1 as key determinants for diastolic function

Obscurin 和 Obsl1 作为舒张功能关键决定因素的作用

• 批准号: 10334533
• 负责人: Yoshitake Cho
• 金额: $ 59.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334533
• 关键词: Accounting; Adult; Affect; Age; Animal Model; Arrhythmia; Binding; Biogenesis; Biological Process; Biopsy; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Cessation of life; Clinical; Data; Development; Diabetes Mellitus; Diagnosis; Diastole; Disease; Disease model; Disease susceptibility; Doppler Echocardiography; EFRAC; Epidemiology; Etiology; Experimental Models; Failure; Fatty Acids; Female; Functional disorder; Gender; Genetic Diseases; Genetic Models; Glucose; Goals; Health; Heart; Heart failure; High Prevalence; Hospitalization; Hypertension; Impairment; Knock-out; Knockout Mice; Longevity; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Target; Mus; Nitric Oxide; Obesity; Onset of illness; Outcome; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Physiologic pulse; Physiological; Physiology; Play; Pre-Clinical Model; Process; Protein Overexpression; Proteins; Proteome; Publishing; RNA Splicing; Reporting; Resolution; Respiratory physiology; Risk Factors; Role; Sarcoplasmic Reticulum; Sex Differences; Signal Transduction; Specific qualifier value; Structure; Syndrome; Telemetry; Testing; Tissues; Transgenic Mice; Work; base; cardiogenesis; comorbidity; connectin; coronary fibrosis; experimental study; heart metabolism; hemodynamics; interest; metabolomics; mitochondrial metabolism; mortality; novel; novel therapeutics; obscurin; overexpression; patient population; pre-clinical; premature; preservation; pressure; protein function; sex; socioeconomics; spatiotemporal; therapy development; uptake

Project Summary: The role of obscurin and Obsl1 as key determinants for diastolic function Cardiovascular disease (CVD) remains a leading cause of mortality in the US, with heart failure accounting for nearly 10% of CVD-related deaths in 2015. Heart Failure with preserved Ejection Fraction (HFpEF) is responsible for half of heart failure hospital admissions, thereby presenting a major health and socioeconomic problem. The diagnosis and development of treatment options for HFpEF remains challenging, due to the diverse patient population, and the high prevalence of heterogenous comorbidities, such as diabetes, obesity or hypertension. Several pathomechanisms have been suggested to play major roles in the development of the disease. However, the dearth of pre-clinical animal models and cardiac patient biopsies that allow for proper characterization of the syndrome complicates the search for molecular pathways and pathomechanisms. We identified that mice lacking obscurin and the closely related obscurin-like 1 (Obsl1) die prematurely and suffer from diastolic dysfunction, a key feature of HFpEF. Based on preliminary data from this novel genetic disease model, we hypothesize that functional insufficiency of the sarcoplasmic reticulum in combination with mitochondrial impairment found in these mice, results in diastolic dysfunction. In this proposal, we aim to establish how loss of obscurin/Obsl1 alters cardiac physiology, metabolism and calcium cycling. Of special interest are novel Obsl1 interaction partners that directly tie functions of this protein to mitochondrial impairment on the molecular level. We will also test if there is a gender divergence in the susceptibility for this disease, as epidemiological HFpEF studies suggest. Outcomes from this project will also determine metabolic and mitochondrial changes in the obscurin/Obsl1 double knockout model that are associated with heart failure development. Finally, we will test if overexpression of Perm1, a master regulator of mitochondrial biogenesis and function is able to alleviate diastolic dysfunction development. Results from this study are expected to establish molecular roles for obscurin/Obsl1 insufficiency in the etiology of diastolic dysfunction and HFpEF, and determine molecular targets for the development of novel therapeutics to treat the disease.

项目总结：obscurin和Obsl 1作为舒张功能关键决定因素的作用 心血管疾病（CVD）仍然是美国死亡的主要原因，其中包括心力衰竭 占2015年CVD相关死亡的近10%。分数保留性心力衰竭 分数（HFpEF）是负责一半的心力衰竭住院，从而提出 一个重大的健康和社会经济问题。诊断和治疗的发展 HFpEF的选择仍然具有挑战性，因为患者人群多样， 异质性合并症的患病率，如糖尿病、肥胖或高血压。几 病理机制已被认为在疾病的发展中起主要作用。 然而，缺乏临床前动物模型和心脏病患者活检， 对该综合征的正确表征使分子途径的研究复杂化， 病理机制 我们艾德缺乏obscurin和密切相关的obscuri-like 1（Obsl 1）的小鼠死亡。 舒张功能障碍是HFpEF的一个关键特征。基于 从这个新的遗传疾病模型的初步数据，我们假设，功能 发现肌浆网不全伴线粒体损伤 导致心脏舒张功能障碍。在本建议中，我们的目标是确定如何损失 obscurin/Obsl 1改变心脏生理学、代谢和钙循环。特别关注的 是新的Obsl 1相互作用伙伴，直接将这种蛋白质的功能与线粒体 分子水平上的损伤。我们还将测试是否存在性别差异， 流行病学HFpEF研究表明，这种疾病的易感性。由此产生的结果 该项目还将确定obscurin/Obsl 1双链中的代谢和线粒体变化， 与心力衰竭发展相关的基因敲除模型。最后，我们将测试 Perm 1是线粒体生物发生和功能的主要调节因子， 以减轻舒张功能障碍的发展。 本研究的结果有望确立obscurin/Obsl 1的分子作用 舒张功能障碍和HFpEF病因学的不确定性，并确定分子 为开发治疗该疾病的新疗法提供了靶点。