A New Pathway for Reversing Cardiac Aging

 描述（由申请人提供）：了解心脏衰老的病理生理学从未如此重要。我们最近发现TGF β家族成员GDF11是一种与年龄相关的激素，与老年小鼠相比，年轻小鼠血液中的GDF11水平增加。在老年动物中增加GDF11的有益效果并不限于心脏，因为我们的研究表明，向老年小鼠施用GDF11可以恢复骨骼肌功能以及大脑中的血管生成。这些新数据表明，系统性GDF11可能在哺乳动物中提供恒定的信号传导，并且这种蛋白质水平的变化可能随着年龄的增长而调节器官功能。虽然想象给予GDF11可以改善具有低水平GDF11的人在年龄相关疾病中的功能是有吸引力的，但关键的是首先考虑在成年哺乳动物心肌的背景下几乎对紧张性GDF11信号传导一无所知。我们的新发现表明，GDF11，以前被认为是胚胎发育的形态原，在成年哺乳动物中提供了以前未被认识到的系统性和紧张性信号。因此，关键是要了解这一点的获得和损失的影响， 心肌中的紧张性信号。在这里，使用蛋白质治疗来增加紧张性GDF11信号传导和使用小鼠中GDF11的诱导性遗传丢失，我们将追求以下假设检验目标，我们认为这对于理解衰老心肌中的GDF11通路是必不可少的：目标1：检验紧张性GDF11信号传导控制心肌细胞萎缩通路的假设。在这里，我们将确定GDF11是否在体外和体内激活心肌细胞中的分子萎缩途径。我们将使用心肌细胞特异性缺失Alk4、SMAD2和SMAD3的小鼠来确定心脏中的GDF11信号传导是否通过经典信号传导途径。我们还将使用小鼠中GDF11的可诱导全身性损失以及心肌细胞特异性GDF11损失来确定紧张性GDF11信号传导的损失是否改变这些途径。 目标二：为了验证紧张性GDF11信号调节年轻和老年小鼠横主动脉缩窄（TAC）后心脏肥大反应的假设。GDF11可以在没有压力超负荷的情况下逆转年龄相关的心脏肥大，但对压力超负荷肥大的影响尚不清楚。在这里，我们将测试的假设，增加紧张性GDF11（重组蛋白）或减少紧张性GDF11（诱导基因丢失的GDF11）后，TAC可以调节心脏肥大。此外，将通过离体和体内测量评价左心室的舒张特性。 目的3：检验小鼠中的紧张性GDF11信号传导减少运动诱导的心脏肥大的假设。在这里，我们将测试的假设，全身增益和损失的紧张性GDF11信号将减少运动诱导的心脏肥大的年轻和老年小鼠。在典型的TGF β信号传导途径中具有缺失的小鼠将确定被激活的特定分子途径。

 DESCRIPTION (provided by applicant): Understanding the pathophysiology of cardiac aging has never been more important. We recently identified the TGFß family member GDF11 as an age-related hormone, with increased levels of GDF11 in the blood of young mice compared to old mice. The beneficial effect of increasing GDF11 in old animals is not limited to the heart, as our studies show that administration of GDF11 to old mice can restore skeletal muscle function as well as angiogenesis in the brain. These new data indicate that systemic GDF11 may provide constant signaling in mammals, and changes in the level of this protein may regulate organ function with advancing age. While it is attractive to imagine that administration of GDF11 could improve function in age- related diseases in humans with low levels of GDF11, it is critical first to consider that almost nothing is known about tonic GDF11 signaling in the context of adult mammalian myocardium. Our new findings show that GDF11, previously considered as a morphogen for embryonic development, provides previously unrecognized systemic and tonic signaling in adult mammals. Thus, it is critical to understand the effects of gain and loss of this tonic signaling in the myocardium. Here, using protein therapy to increase tonic GDF11 signaling and using inducible genetic loss of GDF11 in mice, we will pursue the following hypothesis-testing Aims, which we believe are essential for understanding the GDF11 pathway in aging myocardium: Aim 1: To test the hypothesis that tonic GDF11 signaling controls cardiomyocyte atrophic pathways. Here we will determine if GDF11 activates molecular atrophy pathways in cardiomyocytes in vitro and in vivo. We will determine if GDF11 signaling in the heart is through canonical signaling pathways using mice with cardiomyocyte-specific deletions of Alk4, SMAD2, and SMAD3. We will also determine if loss of tonic GDF11 signaling changes these pathways using inducible systemic loss of GDF11 as well as cardiomyocyte- specific loss of GDF11 in mice. Aim 2: To test the hypothesis that tonic GDF11 signaling regulates the cardiac hypertrophy response after transverse aortic constriction (TAC) in young and old mice. GDF11 can reverse age- related cardiac hypertrophy in the absence of pressure overload, but the effect on pressure overload hypertrophy is unclear. Here we will test the hypothesis that increasing tonic GDF11 (with recombinant protein) or decreasing tonic GDF11 (with inducible genetic loss of GDF11) after TAC can regulate cardiac hypertrophy. Furthermore, diastolic properties of the left ventricle will be evaluated by ex vivo and in vivo measurements. Aim 3: To test the hypothesis that tonic GDF11 signaling in mice reduces exercise-induced cardiac hypertrophy. Here we will test the hypothesis that systemic gain and loss of tonic GDF11 signaling will reduce exercise-induced cardiac hypertrophy in young and old mice. Mice with deletions in the canonical TGFß signaling pathway will determine the specific molecular pathways that are activated.