Negative regulation of Jagged1 by glycosylation: towards a mechanism-based therapy for Alagille syndrome

糖基化对 Jagged1 的负调控：针对 Alagille 综合征的基于机制的治疗

基本信息

批准号：
9310392
负责人：
Hamed Jafar-Nejad
金额：
$ 44.71万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310392
关键词：
Adult Affect Alagille Syndrome Alpha Cell Animal Model Animals Antisense Oligonucleotides Biliary Biochemical Biological Biological Assay C57BL/6 Mouse Cardiac Cardiovascular system Cell Communication Cell Culture Techniques Cell surface Cells Clinical Clinical Trials Collaborations Data Defect Development Disease Dominant Genetic Conditions Embryonic Development Epithelial Cells Evaluation Exhibits Extracellular Domain Functional disorder Gene Dosage Genes Genetic Genetic Suppression Genetic Transcription Glucose Glycosyltransferase Gene Government Growth Heart Heterozygote Homeostasis Human Impairment Injectable Kidney Ligands Liver Mediating Modeling Molecular Monitor Morbidity - disease rate Mouse Cell Line Mus Muscle Cells Mutation Nature Organ Pathway interactions Patients Persons Pharmacologic Substance Phenotype Play Point Mutation Positioning Attribute Prognostic Factor Regulation Reporting Role Serum Severities Signal Transduction Signaling Molecule Site Skeleton Source Technology Testing Therapeutic Toxic effect Vascular Smooth Muscle base bile duct biliary tract body system data modeling developmental disease differential expression dosage experimental study glycosylation human disease improved insight knock-down liver function mRNA Expression mortality mouse model mutant notch protein novel novel therapeutic intervention postnatal preclinical trial public health relevance skeletal therapeutic target total measurement Bilirubin transcription factor transcriptome sequencing

项目摘要

Summary Notch signaling is a cell-to-cell communication mechanism critical for embryonic development and adult homeostasis. To communicate information between cells, Notch receptors on a given cell need to be activated by ligands from neighboring cells. One of the Notch pathway ligands with broad biological roles is called jagged1. Heterozygosity for the jagged1 gene in humans results in Alagille syndrome, which is a multisystem developmental disorder characterized by bile duct abnormalities and defects in other organs systems including the cardiovascular system, kidney and skeleton. The clinical presentation of Alagille syndrome is extremely variable, even in patients with identical point mutations. Accordingly, it has been proposed that genetic modifiers play an important role in the pathophysiology of this disease. Moreover, no mechanism-based treatment has yet been established for Alagille syndrome. We have recently reported a mouse model for Alagille syndrome and have identified the glycosyltransferase gene Poglut1 as a dominant genetic suppressor of the phenotypes in this model. In this proposal, we will use biochemical and cell culture assays, transcriptional profiling and mouse genetic experiments to determine the mechanism of jagged1 regulation by glycosylation and to identify critical targets of jagged1 during bile duct development. We will also use our preliminary data and mouse model as a basis to establish a potential therapeutic approach for Alagille syndrome. These studies have the potential to provide novel insight into the pathophysiology of this disease and the molecular mechanisms underlying the regulation of jagged1-mediated signaling by glycosylation.

概括 Notch信号传导是对胚胎发育至关重要的细胞间通信机制成人体内平衡。为了在细胞之间传达信息，在给定细胞上需要的缺口受体被相邻细胞的配体激活。宽阔的道路配体之一生物学作用称为锯齿状1。人类中Jagged1基因的杂合性导致阿拉吉尔综合征，这是一种以胆管异常为特征的多系统发育障碍以及其他器官系统中的缺陷，包括心血管系统，肾脏和骨骼。这即使在具有相同点的患者中，阿拉吉尔综合征的临床表现也很大。突变。因此，已经提出，遗传修饰符在这种疾病的病理生理学。此外，尚未建立基于机制的治疗对于阿拉吉综合症。我们最近报告了阿拉吉综合征的小鼠模型，并具有确定糖基转移酶基因poglut1是表型的主要遗传抑制剂在此模型中。在此提案中，我们将使用生化和细胞培养分析，转录分析和小鼠遗传实验以确定通过糖基化调节JAGGED1的机制并确定胆管发育过程中JAGGED1的关键靶标。我们还将使用我们的初步数据和小鼠模型作为建立阿拉吉尔潜在治疗方法的基础综合征。这些研究有潜力提供有关此研究的病理生理学的新颖洞察力疾病和基于调节JAGGED1介导的信号传导的分子机制糖基化。