Delineation of the natural history of Ollier disease and Muffucci syndrome and investigation of their genetic bases

奥利尔病和穆夫奇综合征自然史的描述及其遗传基础的研究

• 批准号: 10611190
• 负责人: Joan C Marini
• 金额: $ 51.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611190
• 关键词: Affect; Benign; Biological Assay; Blood Vessels; Brain; Cells; Characteristics; Chondrogenic Neoplasm; Chondroma; Chondrosarcoma; Clinical; Creativeness; Data; Deformity; Development; Diagnosis; Diagnostic; Disease; Down-Regulation; Enchondromatosis; Evaluation; Family; Family member; Fibroblasts; Fostering; Genes; Genetic; Genetic Transcription; Genome; Genomics; Glioma; Goals; Guidelines; HIF1A gene; Health protection; Heterogeneity; Impairment; Investigation; Knock-in; Knowledge; Location; Luciferases; Maffucci Syndrome; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Neoplasms; Medical; Medical Genetics; Metabolic; Mission; Modeling; Mutate; Natural History; Outcome; Pathway interactions; Patients; Phenotype; Predisposition; Prevalence; Public Health; Recording of previous events; Registries; Research; Resources; Roentgen Rays; Role; Sampling; Specimen; Syndrome; Techniques; Testing; United States National Institutes of Health; Variant; Work; base; biobank; bone; cancer therapy; causal variant; clinical center; clinical phenotype; cohort; comparison control; differential expression; effective therapy; exome sequencing; gain of function; gene discovery; genome sequencing; hypoxia inducible factor 1; innovation; novel; pharmacologic; prevent; proband; sample collection; skeletal abnormality; transcriptome sequencing; tumor; whole genome

PROJECT SUMMARY/ABSTRACT Ollier disease (OD) and Maffucci syndrome (MS) are untreatable, poorly characterized, newly recognized cancer susceptibility syndromes. Their genetic bases and pathways responsible for the formation and progression of benign and malignant tumors are not known. Our long-term goal is to identify pharmacological approaches to treat bone deformities and malignant transformation in patients with OD and MS and to prevent/treat related non- syndromic forms of cancers associated with these conditions. Our central hypothesis in this application is that OD and MS are distinct under-characterized cancer susceptibility syndromes caused by variants in multiple genes that disrupt the HIF-1 pathway. The rationale for our project is that phenotypic characterization and identification of the genetic causes of OD and MS have the potential to offer a strong scientific framework whereby new pharmacological strategies to cancer therapy in these patients and patients with the non-syndromic forms of the same cancers, such as chondrosarcomas and gliomas, can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Comprehensively define the phenotypic features of patients with OD and MS; 2) Discover the causative genes and variants of OD and MS in previously uncharacterized cases; 3) Determine the effect of causative variants of OD or MS in the HIF-1 pathway. We will pursue these aims using an innovative combination of genomic and functional techniques applied to a unique set of deeply phenotyped patients. The proposed research is significant because it will: 1) Define the natural history of novel cancer susceptibility syndromes; 2) Establish a unique OD and MS germline and tumor sample collection for research use; 3) Identify the genetic bases of untreatable cancers, and; 4) Determine the role of the HIF-1 pathway in OD and MS. Our expected outcomes are to define the responsible variants and genes that cause benign and malignant tumor formation in OD and MS and to fully elucidate the phenotypic features and natural history of these disorders. Our results will have an important positive impact providing new opportunities for the development of novel pharmacological therapies to treat patients with these diseases as well as those with related non-syndromic forms of cancers such as of chondrosarcomas and gliomas.

项目总结/摘要 Ollier病（OD）和Maffucci综合征（MS）是一种无法治疗的、特征不明确的、新发现的癌症 易感综合征它们的遗传基础和途径负责的形成和发展， 良性和恶性肿瘤尚不清楚。我们的长期目标是确定药理学方法， 治疗OD和MS患者的骨畸形和恶性转化，并预防/治疗相关的非骨关节炎， 与这些病症相关的癌症的综合征形式。我们在本申请中的中心假设是， OD和MS是不同的未充分表征的癌症易感性综合征，由多个基因的变异引起。 破坏HIF-1通路的基因。我们项目的基本原理是， 确定OD和MS的遗传原因有可能提供一个强有力的科学框架 由此，在这些患者和患有非综合征的患者中的癌症治疗的新药理学策略 可能会出现相同形式的癌症，例如软骨肉瘤和神经胶质瘤。核心假设 将通过追求三个具体目标进行测试：1）全面定义患者的表型特征 与OD和MS; 2）发现致病基因和变异的OD和MS在以前未表征的 3）确定OD或MS的致病变体在HIF-1通路中的作用。我们将继续努力， 目的是利用基因组和功能技术的创新组合，应用于一组独特的深入研究。 表型患者。本文的研究意义在于：1）界定小说的自然史 癌症易感综合征; 2）建立独特的OD和MS种系和肿瘤样本收集， 研究用途; 3）确定无法治疗的癌症的遗传基础; 4）确定HIF-1的作用 我们的预期结果是确定导致OD和MS的负责变异和基因。 良性和恶性肿瘤形成的OD和MS，并充分阐明表型特征和自然 这些疾病的历史。我们的成果将产生重要的积极影响，为 开发新的药理学疗法来治疗患有这些疾病的患者以及患有 相关的非综合征形式的癌症，如软骨肉瘤和神经胶质瘤。