Targeting Chronic Senescence to Restore Tissue Homeostasis in Myhre syndrome

针对慢性衰老以恢复 Myhre 综合征的组织稳态

• 批准号: 10425541
• 负责人: MARK E LINDSAY
• 金额: $ 17.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425541
• 关键词: Adult; Affect; Animal Model; Aortic coarctation; Biological Process; Blood; Cardiovascular system; Cell Aging; Cells; Chronic; Cicatrix; Clinical; Codon Nucleotides; Connective Tissue; Connective Tissue Diseases; Development; Disease; Epithelial; Etiology; Exhibits; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Diseases; Genetic Transcription; Homeostasis; Human; Iatrogenesis; Individual; Intratracheal Intubation; Investigational Drugs; Isoleucine; Knock-in Mouse; Lead; Life; Link; Longevity; MADH4 gene; Measures; Missense Mutation; Modeling; Molecular; Mus; Mutation; Myhre syndrome; Natural regeneration; Operative Surgical Procedures; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Pilot Projects; Quality of life; Rare Diseases; Reporting; Respiratory System; Respiratory physiology; Sampling; Signal Transduction; Skin; Skin Tissue; Stenosis; Structure; Symptoms; System; Testing; Therapeutic; Tissues; age related; attenuation; body system; cell type; de novo mutation; efficacious treatment; efficacy evaluation; fibrogenesis; follow-up; gain of function; gain of function mutation; gastrointestinal system; heart function; mouse model; prevent; scale up; senescence; skin fibrosis; small molecule; stem cell function; stem cells; transcriptome

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.

项目总结: