Mechanistic Ancillary Study to the Natural History Study of ADO2 to Determine Clinical Severity

ADO2 自然史研究的机制辅助研究以确定临床严重程度

基本信息

批准号：
10375070
负责人：
Michael J Econs
金额：
$ 23.12万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375070
关键词：
Affect Age Albers-Schonberg disease Ancillary Study Award Biological Assay Biology Biometry Blindness Bone Density Bone Diseases Bone Resorption Bone necrosis CSF1 gene Cattle Cellular biology Chloride Channels Clinical Clinical Trials Country Data Dentin Disease Disease Marker Dominant-Negative Mutation Endocrinology Family Fracture Gene Mutation Genes Genetic Transcription Genotype Goals Impairment Individual Informatics Internal Medicine Interruption Jaw Maxilla Missense Mutation Mutation National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural History No Evidence of Disease Osteoclasts Osteomyelitis Pancytopenia Parents Participant Pathway interactions Patient Recruitments Patients Pediatrics Penetrance Phenotype Physical therapy Population Property RNA RNA Sequences Radiology Specialty Rare Diseases Research Research Personnel Severities Severity of illness Slice TNFSF11 gene bone cohort design effective therapy hematopoietic cell transplantation monocyte multidisciplinary novel peripheral blood sex targeted treatment transcriptome transcriptome sequencing

项目摘要

Abstract NIAMS Supplement Abstract Autosomal dominant osteopetrosis type 2 (ADO2) is a rare disorder resulting from impaired osteoclastic bone resorption due to mutations in the Chloride Channel 7 gene, which cause disease by a dominant negative mechanism. Penetrance is approximately 66% and disease severity varies widely, even within the same family. Affected individuals typically have at least one significant clinical manifestation including fractures, osteonecrosis, osteomyelitis, blindness, or bone marrow failure. We previously demonstrated that osteoclasts cultured from monocytes of individuals with dominant osteopetrosis had markedly decreased pit resorption compared to osteoclasts isolated from carriers who had the same CLCN7 mutation. The osteoclasts from carriers actually resorbed bone similarly to those from control individuals. These studies demonstrated that osteoclast function, rather than the bone microenvironment, was responsible for the differences in bone between affected individuals and carriers. However, the mechanisms that determine influence disease penetrance and severity are unknown. This study will use a well-characterized cohort of subjects from an ongoing natural history study to study these mechanisms. Specifically, we will perform RNA-sequencing analysis using RNA isolated from osteoclasts from affected individuals, asymptomatic carriers and controls (without CLCN7 mutations) and determine differences in RNA expression to identify pathways/networks that differ between affected individuals, carriers and controls. Successful completion of the proposed aims will provide critical data revealing the pathways/networks determining whether an individual with a CLCN7 mutation clinically manifests with severe features or as a nonpenetrant carrier. In addition to providing important information about basic osteoclast biology, understanding the pathways/networks controlling penetrance and clinical severity will enable us to design targeted therapeutics for ADO2.

摘要 NIAMS 补充抽象的常染色体显性骨硬化症 2 型 (ADO2) 是一种由破骨细胞受损引起的罕见疾病由于氯离子通道 7 基因突变导致的吸收，通过显性失活导致疾病机制。外显率约为 66%，即使在同一家族内，疾病严重程度差异也很大。受影响的个体通常具有至少一种显着的临床表现，包括骨折、骨坏死、骨髓炎、失明或骨髓衰竭。我们之前证明破骨细胞从患有显性骨硬化症的个体的单核细胞培养的结果显着减少了凹陷吸收与从具有相同 CLCN7 突变的携带者中分离的破骨细胞进行比较。破骨细胞来自实际上，携带者的骨吸收与对照个体的骨吸收类似。这些研究表明破骨细胞功能而不是骨微环境是造成骨差异的原因受影响的个人和携带者之间。然而，决定影响疾病的机制外显率和严重程度尚不清楚。这项研究将使用一组来自以下领域的特征良好的受试者正在进行的自然历史研究来研究这些机制。具体来说，我们将进行 RNA 测序使用从受影响个体、无症状携带者和对照的破骨细胞中分离的 RNA 进行分析（没有 CLCN7 突变）并确定 RNA 表达的差异，以确定通路/网络受影响的个体、携带者和对照组之间存在差异。成功完成拟议目标将提供关键数据，揭示确定个体是否患有 CLCN7 的通路/网络突变在临床上表现为严重特征或表现为非渗透性携带者。除了提供有关基本破骨细胞生物学的重要信息，了解控制的途径/网络外显率和临床严重程度将使我们能够设计针对 ADO2 的靶向疗法。