Intersection of Upregulated BMP Signaling & Cellular Mechanotransduction in fibrodysplasia ossificans progressiva (FOP)

上调 BMP 信号转导的交叉点

• 批准号: 9257232
• 负责人: Alexandra Katherine Stanley
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257232
• 关键词: ACVR1 gene; Abnormal Cell; Actins; Affect; Alpha Cell; Area; Atomic Force Microscopy; Biomechanics; Blast Cell; Bone Morphogenetic Proteins; Cartilage; Cell Differentiation process; Cell Lineage; Cell Surface Receptors; Cell model; Cell surface; Cells; Cellular Mechanotransduction; Cellular Morphology; Chondrogenesis; Chromatin; Clinical; Connective and Soft Tissue; Cues; Data; Embryo; Environment; Event; Fibroblasts; Genetic; Hereditary Disease; Heterotopic Ossification; Impairment; Injury; Intervention; Lead; Ligands; Measurement; Mechanics; Mechanoreceptors; Mediating; Mesenchymal; Mesenchymal Stem Cells; Morphology; Mus; Muscle; Muscle satellite cell; Mutation; Natural regeneration; Operative Surgical Procedures; Osteogenesis; Pathologic; Pathway interactions; Patients; Perception; Pharmacologic Substance; Physical environment; Play; Population; Process; Proliferating; Receptor Signaling; Replacement Arthroplasty; Research; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Stress Fibers; Therapeutic; Tissues; Transplantation; bone; bone cell; cartilage cell; experimental study; gain of function; gain of function mutation; gene induction; in vivo; injured; insight; lipid biosynthesis; mechanotransduction; mouse model; muscle regeneration; myogenesis; non-genetic; osteogenic; progenitor; progressive myositis ossificans; receptor; receptor function; repaired; response; response to injury; rho; rhoA GTP-Binding Protein; soft tissue; stem cells; therapeutic target; tissue regeneration; tissue trauma; wound healing

Project Summary Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by the formation of extra-skeletal bone known as heterotopic ossification (HO). HO is caused by a series of cellular and tissue- wide events that lead to bone formation within skeletal muscle and other soft connective tissues. All familial and sporadic cases with a classic clinical presentation of FOP carry a gain-of-function heterozygous mutation in ACVR1 (R206H; c.617G>A), a cell surface receptor that mediates bone morphogenetic protein (BMP) signaling, which has been recognized for its chondro- and osteogenic-induction potential. The heterotopic bone that forms in FOP patients is qualitatively normal endochondral bone, however initiation of this bone formation occurs as a result of misdirected cell fate decisions within the affected tissue. HO can form both spontaneously and after injury to the muscle or other soft connective tissue. In addition to ligand-receptor signaling, mechanical cues derived from the physical environment also direct cell fate decisions, with stiff substrates promoting chondrogenic and osteogenic fates and softer substrates promoting neurogenic, adipogenic, and myogenic cell fates. We have observed increased activation of cellular mechanotransduction in progenitor cells harboring the FOP mutation. This proposal seeks to identify the influence of elevated BMP signaling conferred by the Acvr1R206H mutation on cellular mechanical signal transduction (also known as mechanotransduction) and how it affects the ability of muscle stem cells (MuSCs) to regenerate skeletal muscle after injury. I will first determine whether elevated BMP signaling in Acvr1R206H cells interacts with mechanical signaling pathways to alter response to substrate stiffness leading to aberrant cell fate decisions by mesenchymal stem cells (MSCs) (Aim 1). I will also investigate the effect of the Acvr1R206H mutation on the ability of a muscle tissue cell population, muscle stem cells (MuSCs), to repair damaged skeletal muscle tissue (Aim 2). While FOP is a rare genetic disease, HO is a common pathological response to severe tissue trauma scenarios such as blast-initiated injuries and joint- replacement surgeries. Developing a better understanding of HO from a genetic perspective could provide insight into the aberrant mechanisms regulating bone formation and provide targets for pharmaceutical intervention in both genetic and non-genetic causes of HO. Additionally, insights gained from this study will provide us with a better understanding of cellular mechanotransduction and its role in muscle regeneration after injury.

项目总结