Jouberin and Nephrocystin in Joubert Syndrome

Jouberin 和肾囊肿素治疗 Joubert 综合征

• 批准号: 8537515
• 负责人: JOSEPH G GLEESON
• 金额: $ 31.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537515
• 关键词: Affect; Antibodies; Ataxia; Autistic Disorder; Biochemical; Biological; Biology; Blindness; Brain; Brain Diseases; Cell Culture Techniques; Cell Line; Cells; Cellular Membrane; Cellular biology; Cerebellar Diseases; Childhood; Cilia; Complex; Defect; Development; Digit structure; Disease; Dorsal; Erinaceidae; Event; Eye; Funding; Genes; Genetic; Genetic Models; Goals; Hair; Homeostasis; Human; Incidence; Integral Membrane Protein; Joubert syndrome; Kidney; Kidney Failure; Knock-out; Knockout Mice; Lead; Learning; Life; Liver; Liver Fibrosis; Lung; Magnetic Resonance Imaging; Mediating; Membrane; Mental Retardation; Midbrain structure; Modeling; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Mutate; Mutation; Nephronophthisis; Neurodevelopmental Disorder; Organ; Pathogenesis; Pathway interactions; Patients; Phosphatidylinositols; Physiological; Plant Roots; Platelet-Derived Growth Factor; Play; Polydactyly; Positioning Attribute; Post-Translational Protein Processing; Pregnancy Outcome; Proteins; Publishing; Regulation; Retinal; Rhodopsin; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Structure; Structure-Activity Relationship; Technology; Termination of pregnancy; Testing; Tubulin; Work; Zebrafish; base; cellular imaging; ciliopathy; cilium biogenesis; developmental disease; expression vector; fetal; gene function; hindbrain; human disease; improved; kinetosome; mouse model; mutant; nephrogenesis; photoreceptor degeneration; programs; public health relevance; trafficking; unpublished works

DESCRIPTION (provided by applicant): The ciliopathies represent an emerging class of human developmental disorders affecting brain, eye, liver, kidney, digit, skeletal muscle, and lung, all united by disruption of structure or function of the primary cilium. Joubert syndrome (JS) is a ciliopathy, characterized by structural brain anomalies, mental retardation and ataxia, with frequent accompanying retinal blindness, renal failure, polydactyly and hepatic fibrosis. Identifying the pathogenic mechanisms of JS is important for three reasons: 1] A suspicion of a cerebellar disorder frequently leads to pregnancy termination, so understanding these causes can lead to improved predictions about pregnancy outcome. 2] JS has among the highest incidence of co-existent autism among pediatric brain disorders, suggesting what we learn can impact our understanding of more complex disorders. 3] With an improved understanding of basic mechanisms, the field will be in a better position to consider potential treatments. We have identified the genes AHI1, NPHP1, CEP290, ARL13B, and INPP5E as well as several unpublished genes as mutated in patients with JS. We have identified essential signaling functions of these genes in kidney homeostasis, rhodopsin transport, Wnt-, small GTPase-, and phosphatidyl inositol signaling using a combination of mouse modeling, cell biology and biochemical approaches. However, the physiological role of these genes in the pathogenesis of the ciliopathies and the genetic networks remain unknown. The overall goal of this renewal application is to elucidate the developmental, signaling and cell biological mechanisms of the ciliopathy genes underlying the multi- organ involvement in JS, particularly in the context of brain development. We will utilize both traditional and conditional knockout technologies in mouse, genetic modeling in zebrafish, and advanced live-cell imaging capability that will synergize to help advance our understanding of the mechanisms of this important class of disease.

描述（由申请人提供）：纤毛病代表一类新兴的人类发育障碍，影响大脑、眼睛、肝脏、肾脏、手指、骨骼肌和肺，所有这些都通过初级纤毛的结构或功能的破坏而结合在一起。 Joubert 综合征 (JS) 是一种纤毛病，其特征为脑结构异常、智力低下和共济失调，经常伴有视网膜失明、肾功能衰竭、多指畸形和肝纤维化。确定 JS 的致病机制非常重要，原因有以下三个： 1] 对小脑疾病的怀疑常常导致妊娠终止，因此了解这些原因可以改善对妊娠结局的预测。 2] JS 是儿童大脑疾病中共存自闭症发病率最高的疾病之一，这表明我们所学到的知识可以影响我们对更复杂疾病的理解。 3] 随着对基本机制的进一步了解，该领域将能够更好地考虑潜在的治疗方法。 我们已经鉴定出 JS 患者中发生突变的基因 AHI1、NPHP1、CEP290、ARL13B 和 INPP5E 以及几个未发表的基因。我们结合小鼠模型、细胞生物学和生化方法，确定了这些基因在肾脏稳态、视紫红质转运、Wnt-、小 GTPase-和磷脂酰肌醇信号传导中的重要信号传导功能。然而，这些基因在纤毛病发病机制和遗传网络中的生理作用仍然未知。这项更新申请的总体目标是阐明 JS 多器官参与背后的纤毛病基因的发育、信号传导和细胞生物学机制，特别是在大脑发育的背景下。我们将利用小鼠的传统和条件敲除技术、斑马鱼的遗传建模以及先进的活细胞成像能力，这些技术将协同作用，帮助加深我们对这一类重要疾病机制的理解。