CILIA IN EYE DEVELOPMENT AND DISEASE

纤毛与眼睛发育和疾病的关系

基本信息

批准号：
7810578
负责人：
JAREMA MALICKI
金额：
$ 40.55万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7810578
关键词：
Active Biological Transport Affect Afferent Neurons Alleles Amino Acids Anosmia Apical Bardet-Biedl Syndrome Binding Biological Models Blindness Carrier Proteins Cell Death Cells Cellular Structures Cilia Clinical Coiled-Coil Domain Collection Defect Development Developmental Process Disease Elements Endoplasmic Reticulum Enzymes Eye Development Family Fibrinogen Genes Genetic Genetic Screening Goals Human Interphase Cell Intracellular Transport Invertebrates Kidney Kidney Diseases Lead Light Maintenance Mediating Membrane Mental Retardation Missense Mutation Mitotic Molecular Molecular Genetics Monomeric GTP-Binding Proteins Mutation Nature Nervous system structure Neurons Obesity Opsin Other Genetics Pathway interactions Phenotype Photoreceptors Phototransduction Play Polydactyly Process Proteins Role Route Sensory Staging Structure Testing The Sun Transport Vesicles Vertebrate Photoreceptors Vertebrates Vesicle Visual system structure Yeasts Zebrafish cilium biogenesis constriction human disease member mutant neuronal cell body particle photoreceptor disc polypeptide positional cloning protein structure rab GTP-Binding Proteins research study reticulum cell trafficking yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Cilia play an essential role in many developmental processes. In the context of the nervous system, cilia are a key structural component of sensory neurons in both vertebrates and invertebrates. In the vertebrate visual system, the photosensitive component of the cell, known as the outer segment, connects to the rest of the cell body via a narrow constriction that tightly surrounds a ciliary axoneme, and is referred to as the connecting cilium. In the absence of this cilium, the photoreceptor outer segment does not form. A growing body of evidence indicates that ciliary defects cause Bardet-Biedl Syndrome (BBS), a group of human disorders that involve photoreceptor loss and consequently blindness. The clinical manifestations of BBS also involve polydactyly, obesity, kidney disease, anosmia, and mental retardation. To understand the role of cilia in photoreceptor differentiation and disease, we are planning to take both forward and reverse genetic approaches. In a large-scale genetic screen, we identified mutations in the elipsa gene that lead to early loss of cilia, the absence of outer segment formation, and subsequently photoreceptor cell death and blindness. We propose to apply molecular and genetic approaches to study the role of elipsa in photoreceptor differentiation and survival. To carry out its function, Elipsa most likely interacts with other proteins. To determine their identity, we used a molecular genetic approach known as the yeast two-hybrid screen. This effort led to the isolation of several factors, one of which is known to function as an effector of an enzyme family that regulates the trafficking of intracellular vesicles. We are planning to capitalize on this finding to study the intracellular trafficking in the photoreceptor cell - a process known to be of paramount importance of photoreceptor function and survival. In parallel to these efforts, we will apply a complementary reverse genetic approach to study ciliogenesis. Using this approach, known as TILLING, we will generate zebrafish mutants of selected BBS genes. The mutant strains will allow us to study in the detail the role of BBS genes in cilia formation and maintenance, as well as their relationship to other genetic pathways involved in ciliogenesis. The results of these studies will enhance our ability to produce treatment for photoreceptor loss in photoreceptor disorders.

描述（由申请人提供）：Cilia在许多发展过程中起着至关重要的作用。在神经系统的背景下，纤毛是脊椎动物和无脊椎动物中感觉神经元的关键结构成分。在脊椎动物的视觉系统中，细胞的光敏成分（称为外部段）通过狭窄围绕纤毛轴突的狭窄收缩连接到细胞体的其余部分，并称为连接纤毛。在没有纤毛的情况下，光感受器的外部段未形成。越来越多的证据表明，睫状缺陷引起了Bardet-Biedl综合征（BBS），Bardet-Biedl综合征（BBS）是一组涉及感光受体丧失并因此失明的人类疾病。 BBS的临床表现也涉及多态度，肥胖，肾脏疾病，厌食和智力低下。为了了解纤毛在光感受器分化和疾病中的作用，我们计划采用前进和逆转遗传方法。在大规模的遗传筛选中，我们确定了ELIPSA基因中的突变，导致纤毛的早期丧失，缺乏外部段形成以及随后的光感受器细胞死亡和失明。我们建议采用分子和遗传方法来研究ELIPSA在感光细胞分化和存活中的作用。为了执行其功能，Elipsa很可能与其他蛋白质相互作用。为了确定其身份，我们使用了一种分子遗传学方法，称为酵母两杂化筛选。这种努力导致了几个因素的分离，其中一个因素被称为调节细胞内囊泡运输的酶家族的效应因子。我们正计划利用这一发现，以研究光感受器细胞中细胞内运输 - 这一过程已知，这对于感光体功能和生存至关重要。与这些努力并行，我们将采用互补的反向遗传方法来研究纤毛生成。使用这种方法称为耕作，我们将生成选定BBS基因的斑马鱼突变体。突变菌株将使我们能够详细研究BBS基因在纤毛形成和维持中的作用，以及它们与纤毛生成所涉及的其他遗传途径的关系。这些研究的结果将增强我们产生光感受器疾病中光感受器丧失的治疗能力。