Role of the Foxe3 Gene Family in Lens Formation.

Foxe3 基因家族在晶状体形成中的作用。

• 批准号: 8181110
• 负责人: MILAN Alexander JAMRICH
• 金额: $ 39.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181110
• 关键词: Affect; Anterior; Cells; Defect; Development; Developmental Biology; Developmental Gene; Developmental Process; Diagnosis; Diagnostic Procedure; Ectoderm; Epithelium; Event; Eye Development; Eye diseases; Gene Expression Profile; Gene Family; Gene Targeting; Genes; Goals; Head; Human; Knowledge; Lead; Lens Fiber; Lens Placodes; Maintenance; Mammals; Mediating; Mediator of activation protein; Molecular; Molecular Biology; Morphology; Mus; Mutant Strains Mice; Mutate; Mutation; Neuroectoderm; Optic vesicle; Physiology; Play; RNA Sequences; Research; Retinal; Role; Staging; Surface Ectoderm; Techniques; Undifferentiated; Vesicle; Vision; chromatin immunoprecipitation; fiber cell; gene therapy; in utero; lens; mutant; novel diagnostics; transcription factor

DESCRIPTION (provided by applicant): During early vertebrate development, lens is induced to form from the head surface ectoderm by the presumptive retinal neuroectoderm. When the evaginating optic vesicle contacts the surface ectoderm, the ectoderm thickens and forms a lens placode. In mammals, the lens placode invaginates and forms the lens vesicle. The posterior lens cells stop proliferation and differentiate into lens fiber cells. The anterior lens cells form a relatively undifferentiated, proliferatively active lens epithelium. Our long-term goal is to identify developmental steps and molecular events necessary for lens formation. The primary focus of this research is the role and the mechanism of action of the forkhead gene Foxe3. This research is a natural continuation of our previous studies investigating the role of this gene in lens formation. Since normal development and maintenance of lens cells is critical for vision, it is essential to define the developmental processes and gene networks that govern the development and survival of lens cells. Several key genes control of the formation, proliferation and differentiation of lens cells. One of them is the forkhead gene Foxe3. This gene encodes a transcription factor and mutations in this gene cause abnormal lens development in mouse and human. The absence of Foxe3 function leads to changes in the proliferation, differentiation and survival of lens cells. How the loss of Foxe3 leads to all of these changes remains largely unknown. Since Foxe3 is a transcription factor, its effects on the physiology and morphology of lens cells has to be mediated by other genes. With few exceptions, the downstream mediators of Foxe3 are not known. To better understand how Foxe3 regulates lens development and why mutations in this gene lead to such dramatically abnormal lens development, we will in Specific Aim 1 identify genes that belong to the Foxe3 lens regulatory network by comparing transcriptomes of wild type and Foxe3-deficient lenses using deep RNA-sequencing. In Specific Aim 2, we will identify direct target genes of Foxe3 by chromatin immunoprecipitation combined with sequencing. These cutting edge techniques in molecular and developmental biology will help us identify genes that mediate Foxe3 function during lens development. In Specific Aim 3, we will correct the molecular and phenotypic lens defects in mice with mutant or absent Foxe3 using in utero gene therapy. This research will lead to a better understanding of lens development, as this gene is regulating the early critical steps in lens formation. However, since mutations in this gene cause abnormal eye development in mouse and human, this research will result in knowledge that will allow a better diagnosis and treatment of diseases of the eye in which the components of the Foxe3 regulatory network are mutated. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify genes and developmental processes that are responsible for mammalian lens development. Identification of these genes and developmental processes will lead to the better understanding of eye diseases. As a result, new diagnostic procedures and treatments for eye diseases will be developed.

描述（由申请人提供）：在早期脊椎动物发育过程中，假定的视网膜神经外胚层诱导头部表面外胚层形成晶状体。当外翻的视神经泡接触表面外胚层时，外胚层增厚并形成晶状体基板。在哺乳动物中，晶状体基板内陷并形成晶状体囊泡。后晶状体细胞停止增殖并分化为晶状体纤维细胞。前晶状体细胞形成相对未分化、增殖活跃的晶状体上皮。我们的长期目标是确定晶状体形成所需的发育步骤和分子事件。本研究的主要焦点是叉头基因 Foxe3 的作用和作用机制。这项研究是我们之前研究该基因在晶状体形成中的作用的自然延续。 由于晶状体细胞的正常发育和维持对视力至关重要，因此有必要定义控制晶状体细胞发育和存活的发育过程和基因网络。几个关键基因控制晶状体细胞的形成、增殖和分化。其中之一是叉头基因 Foxe3。该基因编码转录因子，该基因的突变会导致小鼠和人类的晶状体发育异常。 Foxe3功能的缺失会导致晶状体细胞的增殖、分化和存活发生变化。 Foxe3 的缺失如何导致所有这些变化仍然很大程度上未知。由于Foxe3是一种转录因子，其对晶状体细胞生理和形态的影响必须由其他基因介导。除少数例外，Foxe3 的下游介体尚不清楚。为了更好地了解 Foxe3 如何调节晶状体发育以及为什么该基因的突变会导致晶状体发育如此显着异常，我们将在具体目标 1 中通过比较野生型和 Foxe3 缺陷晶状体的转录组来识别属于 Foxe3 晶状体调节网络的基因深度 RNA 测序。在具体目标2中，我们将通过染色质免疫沉淀结合测序来鉴定Foxe3的直接靶基因。这些分子和发育生物学领域的尖端技术将帮助我们识别在晶状体发育过程中介导 Foxe3 功能的基因。 在具体目标 3 中，我们将使用子宫基因疗法纠正 Foxe3 突变或缺失的小鼠的分子和表型晶状体缺陷。 这项研究将有助于更好地了解晶状体的发育，因为该基因正在调节晶状体形成的早期关键步骤。然而，由于该基因的突变会导致小鼠和人类的眼睛发育异常，因此这项研究将产生新的知识，从而更好地诊断和治疗 Foxe3 调控网络组件发生突变的眼部疾病。 公共健康相关性：该项目的目标是确定负责哺乳动物晶状体发育的基因和发育过程。这些基因和发育过程的鉴定将有助于更好地了解眼部疾病。因此，将开发新的眼部疾病诊断程序和治疗方法。