The Cellular and Molecular Basis of FOP Lesions

FOP 病变的细胞和分子基础

• 批准号: 8651418
• 负责人: FREDERICK Samuel KAPLAN
• 金额: $ 33.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651418
• 关键词: ACVR1 gene; Animal Model; Blood Vessels; Bone Morphogenetic Proteins; Cartilage; Cells; Characteristics; Clinical; Complication; Connective Tissue; Connective Tissue Cells; Connective and Soft Tissue; Craniocerebral Trauma; Data; Development; Disease; Disease Progression; Disease model; Event; Flare; Gene Mutation; Genes; Goals; Head; Heterotopic Ossification; Homology Modeling; Human; Hypoxia; Immune system; In Vitro; Inflammatory; Inherited; Injury; Investigation; Knowledge; Lead; Lesion; Military Personnel; Molecular; Molecular Genetics; Multiple Trauma; Mutation; Osteogenesis; Pathway interactions; Patients; Plague; Play; Population; Process; Proteins; Recurrence; Role; Signal Transduction; Soft Tissue Injuries; Spinal Cord; Staging; Stem cells; Time; Tissues; Trauma; Type I Activin Receptors; Virus Diseases; War; activin A; base; bone; bone morphogenetic protein receptor type I; disability; effective therapy; hip replacement arthroplasty; malformation; motor vehicle injury; mutant; progressive myositis ossificans; public health relevance; receptor; response; skeletal; skeletal disorder; transmission process

DESCRIPTION (provided by applicant): Fibrodysplasia ossificans progressiva (FOP) is a severely disabling human disorder of episodic and extensive heterotopic (extraskeletal) bone formation. This ectopic endochondral ossification forms qualitatively normal bone; the aberration resides within the cellular signals that regulate commitment to the bone formation pathway. We recently discovered that FOP is caused by a recurrent activating mutation in Activin A receptor, type I/Activin-like kinase2 (ACVR1/ALK2), a type I bone morphogenetic protein (BMP) receptor, in all patients with a classic clinical presentation of FOP. Our data support that this mutation (ACVR1 c.617G>A; R206H) is an activating mutation that signals in part through a BMP-independent mechanism. While the discovery of this genetic mutation is rapidly leading to an understanding of the genetic and molecular cause of FOP, little is known about the cellular origins of FOP lesions or the tissue microenvironment that supports episodic lesion formation. Clinical observations in our FOP patients and preliminary data in our FOP animal models suggest a disease model in which an inflammatory microenvironment caused by soft tissue injury mobilizes resident Tie2+ connective tissue progenitor cells of vascular origin. Further, our preliminary in vitro studies and protein homology modeling predict that the mutant ACVR1/ALK2 receptor up-regulates BMP signaling through a hypoxia-regulated pH-sensitive switch in the mutant receptor. Our central hypothesis is that an activated immune system interacts with the soft connective tissue microenvironment and resident chondro/osseous progenitor cells, in association with the highly specific FOP ACVR1 gene mutation, to induce heterotopic ossification in FOP. We propose to investigate the cellular and microenvironmental conditions that induce the formation of FOP lesions through three specific aims. Aim 1: Identify the inflammatory cells (and associated factors) that activate heterotopic ossification in a background of enhanced BMP signaling. Aim 2: Determine if cells expressing both Tie2 and mature endothelial markers differentiate to cartilage and bone during heterotopic ossification. Aim 3: Determine whether a) hypoxia increases BMP signaling by the mutant ACVR1/ALK2 receptor in FOP cells, and b) whether this effect is due, in part, to an acidic intracellular microenvironment that activates the mutant ACVR1/ALK2 receptor. These investigations will provide critical information for understanding the process of heterotopic bone formation, a serious clinical complication that is relevant not only to FOP but also to patients with more common forms of heterotopic ossification that form after head injuries, motor vehicle accidents, hip replacements, multiple trauma, and war wounds. This knowledge will contribute to our long-term goal of developing more effective treatments for FOP and other disorders of heterotopic ossification.

描述（由申请人提供）：进行性骨化性纤维发育不良（FOP）是一种严重致残的人类疾病，具有偶发性和广泛的异位（骨骼外）骨形成。这种异位软骨内骨化形成质量正常的骨；这种畸变存在于调节骨形成途径的细胞信号中。我们最近发现，在所有具有典型临床表现的患者中，FOP 是由激活素 A 受体、I 型/激活素样激酶 2 (ACVR1/ALK2)（一种 I 型骨形态发生蛋白 (BMP) 受体）的反复激活突变引起的FOP。我们的数据支持这种突变 (ACVR1 c.617G>A; R206H) 是一种激活突变，部分通过 BMP 独立机制发出信号。虽然这种基因突变的发现迅速促进了对 FOP 遗传和分子原因的了解，但人们对 FOP 病变的细胞起源或支持偶发性病变形成的组织微环境知之甚少。我们的 FOP 患者的临床观察和 FOP 动物模型的初步数据表明，在一种疾病模型中，软组织损伤引起的炎症微环境动员了血管来源的常驻 Tie2+ 结缔组织祖细胞。此外，我们的初步体外研究和蛋白质同源性模型预测，突变型 ACVR1/ALK2 受体通过突变型受体中缺氧调节的 pH 敏感开关上调 BMP 信号传导。我们的中心假设是，激活的免疫系统与软结缔组织微环境和驻留软骨/骨祖细胞相互作用，与高度特异性的 FOP ACVR1 基因突变相关，从而诱导 FOP 的异位骨化。我们建议通过三个具体目标来研究诱导 FOP 病变形成的细胞和微环境条件。目标 1：识别在增强的 BMP 信号传导背景下激活异位骨化的炎症细胞（和相关因子）。目标 2：确定同时表达 Tie2 和成熟内皮标记物的细胞在异位骨化过程中是否分化为软骨和骨。目标 3：确定 a) 缺氧是否会增加 FOP 细胞中突变型 ACVR1/ALK2 受体的 BMP 信号传导，以及 b) 这种效应是否部分归因于激活突变型 ACVR1/ALK2 受体的酸性细胞内微环境。这些研究将为了解异位骨形成过程提供重要信息，异位骨形成是一种严重的临床并发症，不仅与 FOP 有关，而且与头部受伤、机动车事故、髋关节置换术后形成的更常见异位骨化形式的患者有关。多重创伤和战争创伤。这些知识将有助于我们的长期目标，即开发针对 FOP 和其他异位骨化疾病的更有效的治疗方法。

项目成果

Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis.

• DOI: 10.1242/dmm.010280
• 发表时间: 2012-11
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Kaplan FS;Chakkalakal SA;Shore EM
• 通讯作者: Shore EM

Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance.

对所谓的 NOGGIN 突变 G92E 的功能分析反驳了其致病相关性。

• DOI: 10.1371/journal.pone.0035062
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zimmer,Julia;Doelken,SandraC;Horn,Denise;Groppe,JayC;Shore,EileenM;Kaplan,FrederickS;Seemann,Petra
• 通讯作者: Seemann,Petra

Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva.

• DOI: 10.1097/01.blo.0000030075.92399.11
• 发表时间: 2003
• 期刊: Clinical orthopaedics and related research
• 影响因子: 4.2
• 作者: Jaimo Ahn;G. Feldman;L. Terry;E. Shore;F. Kaplan

Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling.

• DOI: 10.1002/jbmr.2848
• 发表时间: 2016-09
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Wang, Haitao;Lindborg, Carter;Lounev, Vitali;Kim, Jung-Hoon;McCarrick-Walmsley, Ruth;Xu, Meiqi;Mangiavini, Laura;Groppe, Jay C.;Shore, Eileen M.;Schipani, Ernestina;Kaplan, Frederick S.;Pignolo, Robert J.
• 通讯作者: Pignolo, Robert J.

Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.

• DOI: 10.1002/humu.20868
• 发表时间: 2009-03
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Kaplan, Frederick S;Xu, Meiqi;Seemann, Petra;Connor, J Michael;Glaser, David L;Carroll, Liam;Delai, Patricia;Fastnacht-Urban, Elisabeth;Forman, Stephen J;Gillessen-Kaesbach, Gabriele;Hoover-Fong, Julie;Koster, Bernhard;Pauli, Richard M;Reardon, William;Zaidi, Syed-Adeel;Zasloff, Michael;Morhart, Rolf;Mundlos, Stefan;Groppe, Jay;Shore, Eileen M
• 通讯作者: Shore, Eileen M