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The Cellular Basis of Heterotopic Ossification

异位骨化的细胞基础

基本信息

批准号：
8654253
负责人：
DAVID J GOLDHAMER
金额：
$ 32.08万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-17 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8654253
关键词：
ACVR1 gene Affect Amputation BMP2 gene Biological Assay Bone Matrix Bone Morphogenetic Proteins Cartilage Cell Culture Techniques Cell Transplantation Cell surface Cells Development Dyes Electron Microscopy Endothelial Cells Ensure Exclusion Exclusion Criteria Fluorescence Fluorescence-Activated Cell Sorting Functional disorder Gene Expression Genetic Genetic Recombination Goals Health Hematopoietic Hereditary Disease Heterotopic Ossification Histology Immunofluorescence Immunologic Immunohistochemistry Individual Inflammation Inflammatory Injury Intramuscular Injections Joints Label Lead Lesion Life Life Expectancy Mediating Methodology Methods Modality Modeling Molecular Mus Muscle Mutation Operative Surgical Procedures Osteogenesis Pain Pericytes Peripheral Phosphorylation Physiological Population Prevalence Prevention Prevention strategy Property Quality of life Reporter Reporter Genes Research Role Rotation SCID Mice Severities Signal Transduction Skeletal Muscle Soft Tissue Injuries Sorting - Cell Movement Source Specificity Stem cells Swelling Tamoxifen Technology Testing Therapeutic Time Tissues Total Hip Replacement Transgenic Mice Transplantation Trauma Vascular Smooth Muscle Western Blotting base bone bone morphogenetic protein receptor type I cadherin 5 cell type cellular targeting combat common treatment disability implantation in vivo inclusion criteria matrigel mouse model mutant novel osteogenic progenitor progressive myositis ossificans public health relevance receptor recombinase research study response small molecule soft tissue tool translational study vascular contributions whole body imaging

项目摘要

DESCRIPTION (provided by applicant): Heterotopic ossification (HO), defined as the inappropriate formation of bone in skeletal muscles and associated soft tissues, causes pain, swelling, decreased rotation of affected joints, and other health consequences. HO is a common consequence of certain surgeries and other physical traumas, and also is the defining feature of the severely debilitating condition, fibrodysplasia ossificans progressiva (FOP), a genetic disorder of dysregulated bone morphogenetic protein (BMP) signaling. Despite its prevalence and health consequences, the pathophysiology of HO is poorly understood and the progenitor cells responsible for HO have not been identified. The overarching objective of the proposed research is to identify and characterize the cellular precursors that are responsible for HO. The following hypothesis will be tested: cells of the peripheral vasculature function as osteogenic progenitor cells in response to excessive or dysregulated BMP signaling. In Aims 1 and 2, Cre/lox lineage-tracing methods will be used to determine the contribution of endothelial cells, hematopoietic cells, vascular smooth muscle, pericytes and muscle SP stem cells to HO. HO will be induced by intramuscular injection of BMP2, and the contribution of labeled cell populations to heterotopic cartilage and bone determined by immunohistochemistry using cell-specific markers. In a complementary, independent approach, a cell transplantation bioassay will assess the osteogenic potential of cellular subfractions sorted on the basis of lineage-restricted reporter gene expression, cell surface marker expression or dye exclusion properties (muscle SP). In Aim 3, a genetic mouse model for HO will be developed and characterized. The model is based on Cre recombinase-based conditional expression of the mutant Type I BMP receptor, ACVR1(R206H), which was recently found to cause FOP. In Aim 4, HO in ACVR1(R206H)-expressing mice will be analyzed by whole-body imaging and immunohistochemistry to determine the consequence of cell-specific and temporally controlled expression of the mutant receptor. Effects of injury on the occurrence and severity of ACVR1(R206H)-mediated HO also will be evaluated. These studies will define the cellular progenitors and developmental window in which dysregulated intracellular BMP signaling causes HO. Understanding the cellular basis of HO will identify specific cellular targets and suggest therapeutic strategies for HO. Additionally, the mouse models developed herein will be valuable tools for translational studies aimed at developing and testing small molecule therapies and other modalities for the treatment or prevention of HO.

描述（由申请人提供）：异位骨化（HO），定义为骨骼肌和相关软组织中骨的不适当形成，导致疼痛、肿胀、受影响关节旋转减少和其他健康后果。HO是某些手术和其他身体创伤的常见后果，也是严重衰弱状况进行性骨化纤维发育不良（FOP）的决定性特征，FOP是一种骨形态发生蛋白（BMP）信号失调的遗传疾病。尽管其发病率和健康后果，但对HO的病理生理知之甚少，并且尚未确定负责HO的祖细胞。提出的研究的总体目标是确定和表征负责HO的细胞前体。以下假设将被验证：外周血管细胞作为成骨祖细胞对BMP信号过度或失调的反应。在目标1和目标2中，将使用Cre/lox谱系追踪方法来确定内皮细胞、造血细胞、血管平滑肌、周细胞和肌肉SP干细胞对HO的贡献。肌内注射BMP2诱导HO，使用细胞特异性标记物免疫组化检测标记细胞群对异位软骨和骨的贡献。在一种互补的、独立的方法中，细胞移植生物测定将评估基于谱系限制性报告基因表达、细胞表面标记物表达或染料排除特性（肌肉SP）分类的细胞亚组分的成骨潜力。在第三阶段，将建立和表征一种遗传性小鼠HO模型。该模型基于基于Cre重组酶的I型BMP受体突变体ACVR1（R206H）的条件表达，该突变体最近被发现可引起FOP。在Aim 4中，将通过全身成像和免疫组织化学分析ACVR1（R206H）表达小鼠的HO，以确定突变受体的细胞特异性和暂时控制表达的后果。损伤对ACVR1（R206H）介导的HO发生和严重程度的影响也将被评估。这些研究将确定细胞内BMP信号失调导致HO的细胞祖细胞和发育窗口。了解HO的细胞基础将确定特定的细胞靶点并提出HO的治疗策略。此外，本文开发的小鼠模型将为旨在开发和测试小分子疗法和其他治疗或预防HO的模式的转化研究提供有价值的工具。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stem cells and heterotopic ossification: Lessons from animal models.

DOI：
10.1016/j.bone.2018.01.029
发表时间：
2018-04
期刊：
Bone
影响因子：
4.1
作者：
Lees-Shepard JB;Goldhamer DJ
通讯作者：
Goldhamer DJ

Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.

DOI：
10.7554/elife.40814
发表时间：
2018-09-18
期刊：
eLife
影响因子：
7.7
作者：
Lees-Shepard JB;Nicholas SE;Stoessel SJ;Devarakonda PM;Schneider MJ;Yamamoto M;Goldhamer DJ
通讯作者：
Goldhamer DJ

Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva.

DOI：
10.1038/s41467-018-02872-2
发表时间：
2018-02-02
期刊：
Nature communications
影响因子：
16.6
作者：
Lees-Shepard JB;Yamamoto M;Biswas AA;Stoessel SJ;Nicholas SE;Cogswell CA;Devarakonda PM;Schneider MJ Jr;Cummins SM;Legendre NP;Yamamoto S;Kaartinen V;Hunter JW;Goldhamer DJ
通讯作者：
Goldhamer DJ

Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification.