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

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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.