Targeting collagen 6 for post-infarction recovery

项目摘要 心肌缺血性损伤导致多种结构和功能适应不良 在维修和改建阶段的变化。线粒体功能下降和 胶原沉积增加是缺血后损伤的两个主要特征，以及 两者在组织修复、细胞死亡/存活和长期保存中都发挥着重要作用。 心脏功能。心脏重塑领域传统上主要集中在心脏结构 I型和III型胶原及其在瘢痕形成和异常纤维化中的重要性。我们 有证据表明非纤维素型VI型胶原(Col6)发挥关键作用，但 未被赏识，在心肌梗死后重塑中扮演的角色。Col6协调原纤维的形成和 在几个组织中，I型胶原被固定在基底膜上。 Col6基因突变导致一种众所周知但罕见的骨骼肌病，称为 贝斯拉姆肌病，一种以进行性骨骼肌无力为特征的疾病 由于线粒体通透性转换孔(MPTP)的早期开放和 过早的心肌细胞凋亡。我们实验室开始研究Col6缺乏对小鼠的影响。 利用全球VI型胶原基因敲除(Col6a1-/-)小鼠模型进行心脏移植。给定 已经确定的骨骼肌表型，我们预测Col6的缺失将 导致实验性心肌梗死损伤后心脏重塑的缺陷。我们要做的是 相反，发现了令人惊讶的--Col6基因的敲除具有心脏保护作用：心肌细胞 细胞凋亡、纤维化和左心室扩张减少，长期心功能 被保存在Col6无效的心脏中。这项提案的总体目标是确定 心肌梗死后心肌保护的关键机制 Col6.我们的假设是，VI型胶原基因的敲除可以保护机体免受缺血 通过保存线粒体的结构和功能。我们的具体目标是 建议如下：(1)确定敲除Col6是否保留线粒体 结构和功能，以提供保护免受心肌梗死损伤和(2)沉默Col6 SiRNA作为一种改善心肌梗死后重构和心功能的新疗法。这些 AIMS将阐明这种心脏保护作用和测试的关键机制 体内沉默Col6能否为治疗心肌梗塞提供治疗益处。

Project Summary Ischemic injury in the myocardium causes several maladaptive structural and function changes during the repair and remodeling phases. Decreased mitochondrial function and increased collagen deposition are two major characteristics of post-ischemic injury, and both play major roles in tissue repair, cell death/survival and preservation of long-term cardiac function. The cardiac remodeling field has traditionally focused on the structural types I and III collagen and their importance in scar formation and aberrant fibrosis. We have evidence that the non-fibrillar type VI collagen (Col6) plays a critical, yet unappreciated, role in post-MI remodeling. Col6 orchestrates fibril formation and organization, and anchors type I collagen to the basement membrane in several tissues. Mutations in Col6 cause a well-described but rare skeletal muscle myopathy known as Bethlam Myopathy, a disease characterized by progressive skeletal muscle weakness due to early opening of the mitochondrial permeability transition pore (mPTP) and premature myocyte apoptosis. Our lab began to study effect of Col6 deficiency in the heart by utilizing a global type VI collagen knockout (Col6a1-/-) mouse model. Given the established skeletal muscle phenotype, we predicted that the absence of Col6 would cause deficits in cardiac remodeling following experimentally-induced MI injury. What we found instead was surprising - the knockout of Col6 was cardioprotective: myocyte apoptosis, fibrosis and LV chamber dilation were reduced, and long-term cardiac function was preserved in the Col6 null hearts. The overall goal of this proposal is to determine the critical mechanisms responsible for the post-MI cardioprotection in the absence of Col6. Our hypothesis is that knockout of type VI collagen causes protection from ischemia via preservation of mitochondrial structure and function. The Specific Aims of our proposal are (1) To determine whether knockout of Col6 preserves mitochondrial structure and function to provide protection from MI injury and (2) To silence Col6 with siRNA as a novel therapy to improve post-MI remodeling and cardiac function. These Aims will elucidate the key mechanisms that underlie this cardioprotective effect and test whether silencing Col6 in vivo can provide a therapeutic benefit to treating MI.