A New Pathway for Reversing Cardiac Aging

 描述(由申请人提供)：了解心脏老化的病理生理学从未像现在这样重要。我们最近发现了转化生长因子家族成员GDF11是一种与年龄相关的激素，与老年鼠相比，幼鼠血液中的GDF11水平增加。在老年动物中增加GDF11的有益影响并不局限于心脏，因为我们的研究表明，给老年小鼠注射GDF11可以恢复骨骼肌功能以及大脑中的血管生成。这些新的数据表明，系统的GDF11可能在哺乳动物中提供持续的信号，该蛋白水平的变化可能随着年龄的增长而调节器官功能。尽管想象GDF11的使用可以改善GDF11水平低的人的年龄相关疾病的功能是吸引人的，但关键的是首先要考虑到，几乎对成年哺乳动物心肌中的紧张性GDF11信号一无所知。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知的全身性和紧张性信号。因此，理解这一点的得失的影响是至关重要的。 心肌的紧张性信号。在这里，使用蛋白质疗法增加紧张性GDF11信号，并利用GDF11的可诱导遗传缺失，我们将追求以下假设检验目标，我们认为这是理解老化心肌中GDF11途径的关键：目的1：验证紧张性GDF11信号控制心肌细胞萎缩途径的假说。在这里，我们将确定GDF11是否在体外和体内激活了心肌细胞的分子萎缩途径。我们将使用心肌细胞特异性缺失的Alk4、Smad2和Smad3基因的小鼠来确定心脏中的GDF11信号是否通过规范的信号通路。我们还将利用诱导的全身性GDF11丢失以及小鼠心肌细胞特异性GDF11的丢失来确定紧张性GDF11信号的丢失是否会改变这些通路。目的：验证紧张性GDF11信号调节青年和老年小鼠横断主动脉缩窄(TAC)后心肌肥厚反应的假说。GDF11可在无压力超负荷的情况下逆转增龄性心肌肥厚，但对压力超负荷肥厚的作用尚不清楚。在这里，我们将检验TAC后增加紧张性GDF11(含重组蛋白)或减少紧张性GDF11(伴有可诱导的GDF11基因缺失)可以调节心肌肥厚的假说。此外，还将通过体外和体内测量来评估左心室的舒张性。目的：验证小鼠紧张性GDF11信号抑制运动性心肌肥厚的假说。在这里，我们将检验这一假设，即全身紧张性GDF11信号的获得和丢失将减少运动诱导的年轻和老年小鼠的心肌肥厚。典型的转化生长因子？信号通路缺失的小鼠将决定被激活的特定分子通路。

 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.