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

项目总结：Oblcurin和Obsl1作为舒张期功能的关键决定因素的作用 心血管疾病(CVD)仍然是美国人死亡的主要原因，心力衰竭 占2015年心血管疾病相关死亡人数的近10%。射血功能保留的心力衰竭 分数(HFpEF)负责一半的心力衰竭住院患者，从而呈现 这是一个重大的健康和社会经济问题。治疗的诊断与发展 HFpEF的选择仍然具有挑战性，因为患者群体多样化，而且 异质性合并症的流行，如糖尿病、肥胖症或高血压。几个 病理机制已被认为在疾病的发展中起主要作用。 然而，临床前动物模型和心脏患者活检的缺乏允许 对该综合征的正确描述使寻找分子途径和 病理机制。 我们发现，缺乏黑素和与之密切相关的黑素样蛋白1(Obsl1)的小鼠会死亡 早产和苏醒的舒张期功能障碍，这是高频充盈功能的一个关键特征。基于 来自这个新的遗传病模型的初步数据，我们假设功能 肌浆网ffi异常合并线粒体损伤的研究 在这些小鼠中，会导致舒张期功能障碍。在这项提案中，我们的目标是确定损失如何 Oblcurin/Obsl1改变心脏生理、代谢和钙循环。有特殊利益的人 是新的Obsl1相互作用伙伴，直接将该蛋白质的功能与线粒体联系在一起 分子水平上的损伤。我们还将测试是否存在性别差异 这种疾病的易感性，正如HFpEF流行病学研究所表明的那样。由此产生的结果 该项目还将确定Oblcurin/Obsl1双链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，我们将测试是否 线粒体生物发生和功能的主要调节因子Perm1的过表达 以缓解舒张期功能障碍的发展。 这项研究的结果有望确定Oblcurin/Obsl1的分子作用 ffi在舒张性心功能不全病因中的作用及分子检测 开发治疗该病的新疗法的目标。

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.