Targeting Chronic Senescence to Restore Tissue Homeostasis in Myhre syndrome

点击翻译按钮获取中文摘要

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.