Cherubism and Transforming Growth Factor Beta Signaling

Cherubism 和转化生长因子 Beta 信号传导

• 批准号: 9340122
• 负责人: PETER MAYE
• 金额: $ 23.58万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340122
• 关键词: Adaptor Signaling Protein; Affect; Aftercare; Animal Disease Models; Animal Model; Animals; Arginine; Binding; Biological; Body Weight; Bone Marrow; Cells; Characteristics; Cherubism; Child; Clinical Treatment; Data; Development; Digital Radiography; Disease; Dose; Engineering; Etiology; Face; Future; Genes; Giant Cells; Goals; Histologic; Hyperplasia; Impairment; Inflammation; Knock-in Mouse; Lead; Lesion; Ligands; Link; Mandible; Maxilla; Minerals; Molecular; Mus; Mutation; Osteoclasts; Patients; Phenotype; Phosphorylation; Phosphotransferases; Plasma; Proline; Protein Binding Domain; Rare Diseases; Research; Resolution; Role; SH3 Domains; Series; Serum; Serum Markers; Signal Pathway; Signal Transduction; Signaling Protein; Stromal Cells; Swelling; Symptoms; Testing; Therapeutic; Thinking; Tissues; Transforming Growth Factor beta; Treatment Efficacy; base; bone; cell type; craniofacial; disease phenotype; inhibitor/antagonist; insight; new therapeutic target; novel therapeutics; osteoblast differentiation; prepuberty; protein activation; protein complex; receptor; small molecule; soft tissue; tomography; treatment duration

Cherubism is a rare autosomal dominant craniofacial disorder caused by mutations in SH3-domain binding protein 2 (SH3BP2). This disease affects pre-pubertal children characterized by multilocular lesions in the mandible and/or maxilla consisting of numerous giant multi-nucleated cells with osteoclast like features and extensive fibrous-osseous tissue hyperplasia. Currently, there is no accepted treatment for this disease. Based on certain characteristics of the cherubism phenotype, we suspected that increased TGFβ signaling may have a key role in the presentation of this disease and have used the Sh3bp2KI/KI mice, an animal model for cherubism, to investigate this possibility. Our preliminary studies support a crucial role for the TGFβ signaling pathway in the etiology of cherubism. Bone marrow stromal cultures derived from Sh3bp2KI/KI aberrantly display impaired osteoblast differentiation and robust osteoclast formation. However, when cultures were grown in the presence of antagonists against TGFβ ligands or TGFβ receptor 1, osteoblast differentiation was rescued and osteoclast formation was markedly reduced. Additionally, plasma levels of latent TGFβ1 are nearly 2-fold higher in Sh3bp2KI/KI mice compared to wild type littermates. Based on these preliminary data, we have hypothesized that levels of TGFβ signaling are augmented in cherubism and that reducing TGFβ signaling can be an effective approach to treat cherubism. Therefore, the goals in this application propose to research a previously unexplored connection between SH3BP2 and TGFβ signaling. The aims of this proposal will investigate: (1) whether targeting the TGFβ signaling pathway is an effective therapeutic approach to treat cherubism and (2) how the mutations in SH3BP2 that cause cherubism lead to changes in TGFβ signaling. The information obtained from these studies will yield important information on the therapeutic treatment and biological mechanism of cherubism.

Cherubism是由SH3域突变引起的一种罕见的常染色体显性颅面疾病 结合蛋白2（SH3BP2）。这种疾病会影响以多眼病变为特征的假伯伯纳群岛儿童 下颌骨和/或上颌 广泛的纤维骨组织增生。目前，该疾病尚无接受的治疗方法。 基于Cherubism表型的某些特征，我们怀疑TGFβ信号的增加 在这种疾病的介绍中可能具有关键作用，并使用了动物模型SH3BP2KI/KI小鼠 为了使Cherubism调查这种可能性。 我们的初步研究支持TGFβ信号传导途径在病因中的关键作用 天使。来自SH3BP2KI/Ki的骨髓基质培养物异常显示的成骨细胞受损 分化和稳健的破骨细胞形成。但是，当文化在存在的情况下种植 反对TGFβ配体或TGFβ受体1的拮抗剂，反应成骨细胞分化并反应破骨菌 形成明显减少。另外，潜在TGFβ1的血浆水平在 SH3BP2KI/KI小鼠与野生型同窝仔相比。基于这些初步数据，我们假设 在Cerubism中，TGFβ信号的水平得到了增强，而降低TGFβ信号传导可能是一种 有效治疗基鲁氏症的方法。 因此，本申请建议的目标是研究以前意外的联系 在SH3BP2和TGFβ信号之间。该提案的目的将调查：（1）是否针对 TGFβ信号通路是一种治疗Cherubism的有效治疗方法，（2） 导致Cherubism的SH3BP2导致TGFβ信号的变化。从这些研究中获得的信息 将产生有关Cherubism的治疗和生物学机制的重要信息。