Targeting Chronic Senescence to Restore Tissue Homeostasis in Myhre syndrome

项目总结： Myhre综合征是一种罕见的疾病，由Smad4基因的从头突变引起。 (Ile500密码子Smad4错义突变)。作为一种结缔组织疾病， Myhre综合征的核心症状是危及生命的多发性进行性纤维化 影响结构或功能的器官(结缔组织的增厚和结疤) 心脏、呼吸系统、胃肠系统和皮肤。然而， 像许多其他罕见疾病一样，迈尔综合征仍未得到充分的研究 关于致病性Smad4突变如何导致 无序。特别是，到目前为止还没有可用的治疗这种疾病的方法。 SMAD信号网络控制着大量的生物过程。我们有 先前报道，SMAD信号调节干细胞的功能、谱系 上皮器官的分化和再生(Mou等人，细胞干细胞，2016)。在……里面 这一提议，我们将检验一个假设，即细胞的累积衰老是由 Smad4突变的功能获得是该器官的致病机制之一 Myhre综合征的功能障碍和纤维化。为了验证这一假设，我们最近进行了 开发了一种条件Smad4-I499V敲入小鼠作为生理相关 Myhre综合征模型。在具体目标1中，我们将审查 不同组织的表型、生理和功能变化 整个鼠标寿命。此外，我们将量化与年龄相关的衰老 途径和信号，并检查累积的细胞衰老是否紧密 与进行性纤维化有关。在具体目标2中，我们将使用皮肤纤维化作为模型 并提出了一项初步研究，以测试药物靶向的细胞衰老是否能够 缓解皮肤纤维化。这项研究将为建立 持续性和累积性细胞衰老是该病的致病机制 Myhre综合征的纤维化表现。因此，衰老的早期衰减-- 相关途径或/和消除衰老细胞可能是一种有希望的治疗方法 预防Myhre综合征患者组织纤维化的方法。

Project Summary: Myhre syndrome is a rare disorder caused by de novo mutations in the SMAD4 gene (SMAD4 missense mutation at the codon for Ile500). As a connective tissue disorder, core symptom of Myhre syndrome is life-threatening progressive fibrosis in multiple organs (thickening and scarring of connective tissue) affecting the structure or function of the heart, the respiratory system, the gastrointestinal system, and the skin. However, like many other rare diseases, Myhre syndrome remains significantly understudied with respect to etiologic mechanisms of how pathogenic SMAD4 mutation leads to the disorder. Particularly, there is no available treatment for this disease to date. The SMAD signaling network controls a vast array of biological processes. We have previously reported that SMAD signaling modulates stem cell function, lineage differentiation and regeneration in epithelial organs (Mou et al., Cell Stem Cell, 2016). In this proposal, we will test a hypothesis that the accumulative cell senescence caused by gain-of-function of SMAD4 mutation is one of etiologic mechanisms underlying the organ dysfunction and fibrosis of Myhre syndrome. To test this hypothesis, we have recently developed a conditional SMAD4-I499V knock-in mouse as a physiologically relevant model of Myhre syndrome. In specific aim 1, we will examine the progression of phenotypical, physiological, and functional changes in various tissues throughout the entire mouse lifespan. In addition, we will quantify age-dependent senescence-related pathways and signatures and examine if accumulative cellular senescence is tightly associated with progressive fibrosis. In specific aim 2, we will use skin fibrosis as model and propose a pilot study to test if pharmacological targeting of cell senescence is able to alleviate skin fibrogenesis. This study will provide the scientific evidences to establish the persistent and accumulative cellular senescence as a pathogenic mechanism of the fibrotic manifestations in Myhre syndrome. Thus, the early attenuation of senescence- related pathways or/and elimination of senescent cells can be a promising therapeutic approach to prevent tissue fibrosis in Myhre syndrome patients.