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

基本信息

批准号：
10554438
负责人：
Yoshitake Cho
金额：
$ 58.45万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10554438
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 Fatty Acids Female Functional disorder Gender Genetic Diseases Genetic Models Glucose Goals 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 Relaxation Reporting Resolution Respiratory physiology Risk Factors Role Sarcoplasmic Reticulum Sex Differences Signal Transduction Specific qualifier value Structure Syndrome Telemetry Testing Tissues Transgenic Mice Work comorbidity connectin coronary fibrosis experimental study health economics heart metabolism hemodynamics interest metabolomics mitochondrial metabolism mortality novel novel therapeutics obscurin overexpression patient population pre-clinical premature preservation pressure protein function reuptake sex socioeconomics spatiotemporal therapy development

项目摘要

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.

项目摘要：obscurin 和 Obsl1 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，其中心力衰竭 2015 年，占 CVD 相关死亡人数的近 10%。射血不全的心力衰竭一半的心力衰竭住院病例 (HFpEF) 是造成这种情况的原因重大健康和社会经济问题的诊断和治疗的发展。由于患者群体的多样化以及高风险，HFpEF 的选择仍然具有挑战性。异质合并症的患病率，例如糖尿病、肥胖或高血压。病理机制被认为在该疾病的发展中发挥着重要作用。然而，缺乏临床前动物模型和心脏病患者活检该综合征的正确表征使分子途径的寻找变得复杂病理机制。我们发现缺乏 obscurin 和密切相关的 obscurin-like 1 (Obsl1) 的小鼠会死亡过早出现舒张功能障碍，这是 HFpEF 的一个关键特征。来自这种新型遗传疾病模型的初步数据，我们与功能性发现肌浆网功能不全并伴有线粒体损伤在这些小鼠中，导致舒张功能障碍。在这项提议中，我们的目标是确定舒张功能丧失是如何发生的。 obscurin/Obsl1 改变心脏生理学、代谢和钙循环。是新颖的 Obsl1 相互作用伙伴，直接将该蛋白的功能与线粒体联系起来我们还将测试分子水平上是否存在性别差异。正如流行病学 HFpEF 研究结果所表明的那样，该疾病的易感性。项目还将确定 obscurin/Obsl1 双基因的代谢和线粒体变化最后，我们将测试与心力衰竭发展相关的敲除模型。 Perm1（线粒体生物合成和功能的主要调节因子）的过度表达能够缓解舒张功能障碍的发展。这项研究的结果预计将确定 obscurin/Obsl1 的分子作用舒张功能障碍和 HFpEF 病因学的不足，并确定分子水平开发治疗该疾病的新疗法的目标。