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

基本信息

批准号：
10598638
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
项目类别：
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/10598638
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 Receptors 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 Heterozygote Impairment Injections 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 Resected Role Safety Severities Signal Transduction Signaling Protein Source Structure Syndrome Tamoxifen Testing Therapeutic Tissues Transgenic Mice antagonist autosome 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

项目摘要

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.

遗传多个遗传（HME）是一种罕见的常染色体显性疾病，影响了数千名儿童全世界。 HME的特征是软骨波尼肿瘤，称为骨软骨瘤，形成在内沿生长板的perichondrium伸入并与周围组织碰撞。肿瘤可以因此导致骨骼畸形，神经和血管的压缩以及慢性疼痛大约2-3％的患者恶性肿瘤。当前的疗法有限，患者因疼痛而挣扎，有限流动性并在生活中进行多次手术。大多数HME患者在负责硫酸乙酰肝素（HS）合成的EXT1或EXT2，从而导致部分全身HS 不足。 HS链以及它们部分调节且明显调节的蛋白聚糖许多过程。值得注意的是，它们与包括骨形态发生蛋白（BMP）的信号蛋白相互作用以及刺猬的家庭成员，最常限制和界定蛋白质分布，可用性和活动。但是，尚不清楚这些机制中的哪种机制是否可能在HME中乱七八糟及其如何可能导致肿瘤形成。在上一个资金期间，我们发现Ext1的条件消融导致perichondrium中的促可能性BMP信号的增加，并同时减少抗软骨生成PERK1/2和Noggin，使正常的稳态机制通常保持 perichondrium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个类似生长板的组织，能够在周围的组织上单向生长，从而创造损坏和破坏。我们已经获得了建立IHH-PTHRP轴驱动肿瘤的证据出生。我们的核心假设是骨软骨瘤的发育和出现是由以下方式驱动的：（i） HS的急性局部缺乏；（ii）增加BMP信号传导；（iii）建立Neo IHH-PTHRP循环。作为结果，我们认为骨软骨瘤的发育和生长适合于指示的药物治疗反对这些监管电路的组成部分。我们将使用遗传，生化和细胞方法以及转基因小鼠模型紧密模仿人类疾病的进展和负担。该项目将继续从根本上提供对肿瘤形成的细胞和分子机制以及这些机制在标准的围绕板和生长板细胞中的正常功能。它也将测试基于这些见解的可能疗法，因此具有主要的翻译医学价值和含义。 HME患者的数量相对较小，但他们家庭的社区数量很大。这个项目将因此，为患者和家庭提供了一种新的希望感，这种疾病将继续积极研究并有一天可以找到治愈方法。