Follistatin-like protein 1 in cardiac and systemic metabolism

 描述（由申请人提供）：我们实验室和其他实验室的最新研究表明，心脏和外周之间存在能量底物代谢的复杂交叉调节，由添加到胰岛素、胰高血糖素或其他经典调节剂的肽/蛋白质介导。在潜在的候选调解人，特别值得关注的肌肉释放，肌肉样因子统称为“肌因子”。其中一个新成员是卵泡抑素样蛋白1（Fstl 1），它也是由心脏产生的，正如首次显示的那样 由沃尔什实验室，并因此可以归因于称为“心脏因子”的肌因子亚组。高循环Fstl 1是心力衰竭（HF）的可靠标志物，而如果急性 Fstl 1过表达对心肌缺血再灌注损伤具有保护作用。然而，虽然Fstl 1的分子生物学甚至治疗潜力正在逐步阐明和定义，但实际上对这种激素的综合生理学和病理生理学一无所知。特别是，没有研究探讨Fstl 1作为代谢调节剂的潜在作用。Recchia和沃尔什实验室的初步研究表明，Fstl 1过表达或输注改变了小鼠和狗的心脏和全身代谢。因此，本项目将测试心脏和骨骼肌产生的Fstl 1的相对分数随生理和病理条件的变化而变化，并成比例地促进心脏和全身能量代谢的自分泌和相互内分泌调节的假设。将在犬和小鼠模型中结合研究实现三个具体目标。具体目标1将确定基线时以及对运动或中度和重度HF的响应时心肌和骨骼肌产生Fstl 1的总体周转率和相对速率。这些研究将在静息条件下和运动期间或快速起搏诱导HF发生期间在长期使用仪器的犬中进行。具体目标2将测试Fstl 1是否在生理条件下和HF中调节心脏和全身氧和能量底物消耗。这些研究将在心脏或骨骼肌选择性Fstl 1功能丧失的小鼠模型和长期使用器械的犬中进行。潜在的分子变化和机制将在组织样品中，离体，以及在培养的心肌细胞和骨骼肌纤维暴露于Fstl 1。具体目标3将测试心脏Fstl 1合成的持续、选择性增强是否可以减弱心肌和/或全身代谢改变并在HF中发挥治疗作用。这些研究将在心脏特异性Fstl 1基因敲除小鼠中进行，这些小鼠接受主动脉缩窄，在患有快速起搏诱导的HF的犬中进行，并接受由腺相关病毒载体携带的Fstl 1心脏基因转移。在小鼠和犬中的联合研究可能会将新的发现转化为HF的新生物疗法。

 DESCRIPTION (provided by applicant): Recent studies from our laboratory and others suggest the existence of a complex cross- regulation of energy substrate metabolism between heart and periphery, mediated by peptides/proteins that add to insulin, glucagon or other classical regulators. Among the potential candidate mediators, particular attention deserve muscle-released, hormone-like factors collectively named "myokines". One of the emerging members is follistatin-like protein 1 (Fstl1), which is produced also by the heart, as first showed by the Walsh laboratory, and can be therefore ascribed to the myokine subgroup named "cardiokines". High circulating Fstl1 is a reliable marker of heart failure (HF), while, if acutely overexpressed, Fstl1 can protect the heart against ischemia-reperfusion injury. However, while the molecular biology and even the therapeutic potential of Fstl1 are being progressively elucidated and defined, virtually nothing is known yet about the integrative physiology and pathophysiology of this hormone. In particular, no studies have explored the potential role of Fstl1 as a metabolic modulator. Preliminary studies from Recchia and Walsh labs indicate that Fstl1 overexpression or infusion alters cardiac and systemic metabolism in mice and dogs. Therefore the present project will test the hypothesis that the relative fractions of Fstl1 produce by heart and skeletal muscle vary in response to physiological and pathological conditions and contribute proportionally to the autocrine and the reciprocal endocrine regulation of cardiac and systemic energy metabolism. Three specific aims will be pursued combining studies in dog and mouse models. Specific aim 1 will determine overall turnover and relative rate of Fstl1 production by cardiac and skeletal muscle at baseline and in response to exercise or to moderate and severe HF. These studies will be performed in chronically instrumented dogs under resting conditions and during exercise or the development of tachypacing-induced HF. Specific aim 2 will test whether Fstl1 modulates cardiac and systemic oxygen and energy substrate consumption under physiological conditions and in HF. These studies will be performed in mouse models of cardiac or skeletal muscle- selective Fstl1 loss of function and in chronically instrumented dogs. The underlying molecular changes and mechanisms will be determined in tissue samples, ex vivo, as well as in cultured cardiomyocytes and skeletal myofibers exposed to Fstl1. Specific aim 3 will test whether sustained, selective enhancement of cardiac Fstl1 synthesis can attenuate myocardial and/or systemic metabolic alterations and exert therapeutic effects in HF. These studies will be performed in cardio-specific Fstl1 knockout mice subjected to aortic constriction and in dogs with tachypacing-induced HF and subjected to cardiac gene transfer of Fstl1 carried by adeno- associated viral vectors. Combined studies in mice and dogs may lead to the translation of novel findings into a new biological therapy for HF.