Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome

遗传性多发性外生骨疣综合征的发病机制

• 批准号: 10442054
• 负责人: Maurizio Pacifici
• 金额: $ 38.72万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442054
• 关键词: Ablation; Adolescent; Affect; Agonist; Area; Automobile Driving; Benign; Biochemical; Biological; Biological Availability; Biomedical Research; Bioreactors; Blood Vessels; Bone Morphogenetic Proteins; Cartilaginous exostosis; Cell Lineage; Cell surface; Cells; Child; Childhood; Chondrogenesis; Chondrogenic Neoplasm; Clinical; Communities; Congenital Disorders; Data; Deformity; Development; Diffusion; Diphtheria Toxin; Disease; Disease Progression; Distal; Dose; EXT1 gene; EXT2 gene; Effectiveness; Enzymes; Epiphysial cartilage; Erinaceidae; Exostoses; Extravasation; FDA approved; Family; Family member; Fatigue; Funding; Genetic; Golgi Apparatus; Growth; Growth and Development function; Heparitin Sulfate; Hereditary Multiple Exostoses; Impairment; Injections; Lead; Left; Life; Link; Malignant - descriptor; Modality; Molecular; Monitor; Mus; Mutant Strains Mice; Mutation; Nerve; Nerve compression syndrome; Operative Surgical Procedures; Pain; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Pharmacotherapy; Phenotype; Population; Prevention; Process; Proteins; Proteoglycan; Receptor Signaling; Regimen; Role; Safety; Severities; Signal Transduction; Signaling Protein; Source; Structure; Syndrome; Tamoxifen; Testing; Therapeutic; Tissues; Transgenic Mice; Ursidae Family; antagonist; base; bone morphogenetic protein receptors; burden of illness; cartilaginous; chronic pain; effective therapy; human disease; insight; mouse model; novel; osteogenic protein 2; parathyroid hormone-related protein; prevent; progenitor; protein distribution; receptor; side effect; skeletal; skeletal stem cell; smoothened signaling pathway; stem; therapeutic target; therapeutically effective; translational medicine; tumor

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant disorder that affects thousands of children worldwide. HME is characterized by cartilaginous-bony tumors called osteochondromas that form within perichondrium along growth plates and protrude into and collide with surrounding tissues. The tumors can thus cause skeletal deformities, compression of nerves and blood vessels and chronic pain, and become malignant in about 2-3% of patients. Current therapies are limited, and patients struggle with pain and limited mobility and undergo multiple surgeries through life. Most HME patients bear a heterozygous mutation in EXT1 or EXT2 that are responsible for heparan sulfate (HS) synthesis, thus causing a partial systemic HS deficiency. The HS chains -and the proteoglycans of which they are part- regulate and distinctly modulate many processes. Notably, they interact with signaling proteins including bone morphogenetic proteins (BMPs) and hedgehog family members and most often restrict and delimit protein distribution, availability and activity. However, it is not clear whether and which of these mechanisms may be deranged in HME and how it could lead to tumor formation. In the previous funding period, we found that conditional ablation of Ext1 caused an increase in pro-chondrogenic BMP signaling in perichondrium and a concurrent decrease in anti- chondrogenic pERK1/2 and Noggin, deranging normal homeostatic mechanisms that normally maintain the perichondrium phenotype. In preliminary studies, we have aimed to clarify how the osteochondromas acquire a growth plate-like organization, are able to grow unidirectionally against surrounding tissues and thus create damage and havoc. We have obtained evidence for the establishment of an IHH-PTHrP axis driving tumor outgrowth. Our central hypotheses is that osteochondroma development and outgrowth are driven by: (i) a steep local deficiency in HS; (ii) increased BMP signaling; and (iii) establishment of a neo IHH-PTHrP loop. As a result, we posit that osteochondroma development and growth are amenable to drug treatments directed against components of those regulatory circuits. We will use genetic, biochemical and cellular approaches and transgenic mouse models that closely mimic human disease progression and burden. The project will continue to provide fundamentally new insights into cellular and molecular mechanisms of tumor formation as well as normal functioning of those mechanisms in standard perichondrial and growth plate cells. It will also test possible therapies based on those insights and thus has major translational medicine value and implications. The number of HME patients is relatively small, but the community of their families is large. This project will thus provide a renewed sense of hope to patients and families alike that this disease will continue to be actively studied and a cure may one day be found.

遗传性多发性外生骨疣（HME）是一种罕见的常染色体显性遗传病，影响成千上万的儿童 国际吧HME的特征是软骨骨肿瘤，称为骨软骨瘤， 软骨膜沿着生长板突出并与周围组织碰撞。肿瘤可以 从而导致骨骼畸形、神经和血管受压以及慢性疼痛， 恶性肿瘤约占2-3%。目前的治疗方法是有限的，患者与疼痛和有限的 移动性和经历多次手术贯穿一生。大多数HME患者在基因组中携带杂合突变 负责硫酸乙酰肝素（HS）合成的EXT 1或EXT 2，从而导致部分全身HS 缺陷HS链--以及它们所属的蛋白聚糖--调节并明显调节 许多过程。值得注意的是，它们与包括骨形态发生蛋白（BMP）在内的信号蛋白相互作用。 和刺猬家族成员，最经常限制和界定蛋白质的分布，可用性和 活动然而，目前尚不清楚这些机制中是否以及哪些可能在HME中发生紊乱，以及如何发生紊乱。 可能导致肿瘤形成。在之前的资助期间，我们发现Ext 1的条件性消融 引起软骨膜中促软骨形成BMP信号的增加，同时引起抗软骨形成BMP信号的减少。 软骨形成pERK 1/2和Noggin，扰乱了正常的自我平衡机制，这些机制通常维持软骨形成。 软骨膜表型在初步研究中，我们的目的是阐明骨软骨瘤如何获得 一种生长板状组织，能够在周围组织上单向生长， 破坏和浩劫。我们已经获得了建立IHH-PTHrP轴驱动肿瘤的证据 结果我们的中心假设是，骨软骨瘤的发展和生长是由以下因素驱动的：（i） HS的急剧局部缺陷;（ii）BMP信号传导增加;和（iii）neo IHH-PTHrP环的建立。作为 因此，我们认为骨软骨瘤的发展和生长可以通过药物治疗来控制， 与这些调节电路的组件相对抗。我们将使用遗传学、生物化学和细胞学方法， 转基因小鼠模型，密切模拟人类疾病的进展和负担。该项目将继续 为肿瘤形成的细胞和分子机制提供了全新的见解， 这些机制在标准软骨膜和生长板细胞中的正常功能。它还将测试 基于这些见解的可能疗法，因此具有重大的转化医学价值和影响。 HME患者的数量相对较少，但他们的家庭社区很大。该项目将 从而为患者和家属带来新的希望，即这种疾病将继续活跃， 也许有一天会找到治疗方法。