Molecular and cellular mechanisms of heterotopic ossification

异位骨化的分子和细胞机制

• 批准号: 8538700
• 负责人: PAUL B YU
• 金额: $ 5.98万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538700
• 关键词: ACVR1 gene; Address; Adenoviruses; Adoptive Transfer; Adrenal Cortex Hormones; Affect; Attenuated; Autoimmune Diseases; Biochemical; Birth; Blood Vessels; Bone Marrow; Bone Morphogenetic Proteins; Burn injury; Cells; Complement; Complication; Connective Tissue; Dendritic Cells; Development; Disease; Engraftment; Fracture; Gene Expression; Genetic; Grant; Heart Diseases; Heterotopic Ossification; Human; Immune; Individual; Infection; Inflammation; Inflammatory; Injury; Joints; Kinetics; Lead; Lesion; Ligaments; Ligands; Mediating; Mesenchymal; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle; Mutation; Myositis; Natural Immunity; Natural regeneration; Operative Surgical Procedures; Osteogenesis; Pain; Pathogenesis; Pericytes; Phosphotransferases; Population; Premature Mortality; Process; Proteins; Rare Diseases; Receptor Signaling; Recruitment Activity; Replacement Arthroplasty; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal Muscle Satellite Cells; Stem cells; Stimulus; Syndrome; Techniques; Testing; Tissues; Toll-like receptors; Transgenes; Transgenic Organisms; Trauma; Vascular Diseases; Viral; base; bone; bone morphogenetic protein receptor type I; calcification; cell type; cellular targeting; effective therapy; falls; gain of function; human disease; injury and repair; insight; macrophage; mouse model; mutant; novel; novel strategies; osteogenic; osteoprogenitor cell; postnatal; progenitor; programs; progressive myositis ossificans; receptor; receptor-mediated signaling; recombinase; reconstitution; repaired; response; skeletal abnormality; small molecule; soft tissue

DESCRIPTION (provided by applicant): Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms responsible for HO are not known; however, its association with postsurgical and posttraumatic contexts suggests a process of disordered injury repair. Further insights into the causes of HO may be gained from a congenital HO syndrome, fibrodysplasia ossificans progressiva (FOP). FOP is caused by "constitutively-activating" mutations in the bone morphogenetic protein (BMP) type I receptor ALK2, which result in progressive and widespread joint ossifications triggered by minimal trauma or inflammation. Both FOP and acquired forms of HO lack effective therapies. In fact, there is significant evidence that both FOP and HO are caused by inappropriate activation of the BMP signaling pathway. It is not known how enhanced BMP signaling deviates the injury repair program, or which populations of cells mediate the effects of enhanced BMP signaling. To address these questions we have developed a mouse model of FOP in which a constitutively-active mutant form of ALK2 (caALK2) is inducibly expressed. Similar to affected humans, expression of this gene does not spontaneously induce HO, but vigorous ossification and joint fusion occur with additional stimuli of inflammation and muscle injury. Our subsequent studies with this model suggest that these caALK2 proteins may not be constitutively-active, as previously thought, but may sensitize cells to traditional ligand-mediated BMP signals. In Aim 1 of this grant, we will employ this model to discern the mechanisms by which caALK2 sensitizes cells to BMP signals, testing whether caALK2 requires ligand-mediated signaling or functions independently. To identify the cellular progenitors which mediate the effects of enhanced BMP signaling, and which contribute to the ectopic bone lesions, in Aim 2 we have targeted the expression of mutant caALK2 to several candidate progenitor lineages. Using a complement of cell-based, genetic targeting, and adoptive transfer techniques, we will systematically determine the impact of expressing caALK2 in compartments with known osteogenic potential, including skeletal muscle satellite cells, vascular pericytes, as well as bone-marrow derived lineages. In Aim 3, we examine the role of innate immune signaling in the development of ectopic bone in this model. Understanding how caALK2 mutations alter the consequences of BMP signaling could highlight novel molecular or cellular targets for management of HO. This proposal seeks to elucidate how enhanced BMP signaling impacts mesenchymal progenitors and governs adaptive and maladaptive osteogenesis at the interface of injury, inflammation, and regeneration.

描述（由申请人提供）：异位骨化（HO），骨骼肌和软组织中异位内侧软骨的形成，是关节固定和疼痛发病的重要原因。负责HO的确切机制尚不清楚。但是，它与术后和创伤后环境的关联表明了损伤修复的过程。可能会从先天性HO综合征，纤维状发育异常Progenkhiva（FOP）中获得进一步的见解。 FOP是由骨形态发生蛋白（BMP）I型受体ALK2中的“组成激活”突变引起的，这导致了最小创伤或炎症触发的进行性和广泛的关节骨化。 FOP和获得形式的HO都缺乏有效的疗法。实际上，有大量证据表明，FOP和HO都是由BMP信号通路的不适当激活引起的。尚不知道增强的BMP信号传导如何偏离损伤修复程序，或者哪些细胞种群介导增强的BMP信号传导的影响。为了解决这些问题，我们开发了一种FOP的小鼠模型，在该模型中，ALK2的组成型突变体形式（Caalk2）被诱导地表达。与受影响的人类类似，该基因的表达不会自发诱导HO，但是随着炎症和肌肉损伤的额外刺激，会出现剧烈的骨化和关节融合。我们随后对该模型的研究表明，这些Caalk2蛋白可能不像以前认为的那样活性，但可能会使细胞对传统配体介导的BMP信号敏感。在该赠款的AIM 1中，我们将采用该模型来辨别Caalk2将细胞敏感到BMP信号的机制，从而测试Caalk2是否需要配体介导的信号传导或独立功能。为了鉴定介导增强BMP信号传导影响并有助于异位骨折的细胞祖细胞，在AIM 2中，我们将突变体Caalk2的表达靶向于几个候选祖细胞谱系。使用基于细胞的遗传靶向和收养转移技术的补充，我们将系统地确定在具有已知成骨潜力的隔室中表达Caalk2的影响，包括骨骼肌卫星细胞，血管周细胞细胞，以及骨髓衍生的谱系。在AIM 3中，我们研究了先天免疫信号在该模型中异位骨发育中的作用。了解Caalk2突变如何改变BMP信号的后果可能会突出用于管理HO的新型分子或细胞靶标。该提案旨在阐明增强的BMP信号传导如何影响间充质祖细胞，并控制损伤，炎症和再生的适应性和适应不良的成骨。