Cell-Cell Signaling During Mammalian Early Eye Formation

哺乳动物早期眼睛形成过程中的细胞间信号传导

• 批准号: 7367571
• 负责人: Nadean L Brown
• 金额: $ 37.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367571
• 关键词: Address; Affect; Alagille Syndrome; Alleles; Animals; Aniridia; Anophthalmos; Anterior; Arts; Binding; Biochemical; Cancer Biology; Cancer Etiology; Cataract; Cell Maintenance; Cell Proliferation; Cell Shape; Cell physiology; Cells; Cessation of life; Cornea; Defect; Deformity; Development; Disease; Embryology; Embryonic Development; Ensure; Exhibits; Eye; Eye Development; Genes; Genetic; Genotype; Goals; Grant; Grouping; Growth; Heart; Histology; Human; Immunohistochemistry; In Situ Hybridization; Individual; Investigation; Irido-corneo-trabecular dysgenesis; Ligands; Liver; Microphthalmos; Molecular; Morphogenesis; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Notch Signaling Pathway; Optic vesicle; Organ; Other Body Part; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Polymerase Chain Reaction; Process; Rana; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Skeletal system; Stem cells; Structure; Technology; Testing; Tissues; design; eye formation; fly; in vivo; intercellular communication; jagged1 protein; lens; lens morphogenesis; member; mouse model; mutant; notch protein; optic cup; prenatal; protein protein interaction; receptor; research study; size; tumor

DESCRIPTION (provided by applicant): This proposal investigates the underlying causes of human ocular diseases using mouse models. We focus on the Notch signaling pathway, which is critically required for the formation of multiple mammalian tissues. In particular, Notch signaling regulates proliferation, cell shape changes, differentiation and stem cell maintenance. Because Notch signaling is widely employed during development, mouse mutations in most Notch pathway genes have already been created. Interestingly, Notch1-/-, Notch2-/- and Jagged1 mutant mice each have prenatal eye phenotypes, but little is known about the roles of these genes the early eye. Additionally, dominant human mutations in the Notch ligand Jagged1 cause Alagille syndrome in which some patients exhibit congenital, anterior eye deformities. We have shown that the Notch effector Hes1 is required for mouse lens cell proliferation, and Hes1:Pax6 double mutant mice are anophthalmic. These findings provoke us to understand better the roles of Notch signaling during early eye development, particularly lens formation. Using a combination of targeted deletion mice (wholly mutant and conditional alleles), we propose to determine a) the requirements for Notch signaling during lens and optic vesicle growth and morphogenesis, b) the role of the Notch ligand Jagged1 during lens formation and c) how Notch signaling and Pax6 interact during lens formation. All studies will employ conditional (cre-lox) mouse strains, histology, immunohistochemistry, in situ hybridization, mouse embryology and PCR genotyping. These studies will contribute new information to the processes of growth and morphogenesis, which are fundamental to all metazoan development. We anticipate that these studies will yield a better understanding of Alagille syndrome aniridia, Peter's anomaly, microphthalmia and anophthalmia, Findings here will also be widely useful to the field of cancer biology, since excess activated Notch1, Hes1 or Jagged1 expression occurs in a variety of human tumors. The goal of this study is to understand the underlying molecular mechanisms of how the mammalian lens forms, using mouse models. We propose to do this by investigating which aspects of lens formation require the Notch cell-to-cell signaling pathway. In other parts of the body, Notch signaling controls cell shape changes, growth, and death. For these reasons, mutations in the Notch pathway can cause cancer. A thorough understanding of how, when and where Notch acts in the lens has not been previously addressed. These studies will provide better understanding of how the lens forms and contribute to the better design of disease therapies for lens cataracts and Alagille syndrome.

描述（由申请人提供）：该提案利用小鼠模型研究人类眼部疾病的根本原因。我们重点关注 Notch 信号通路，该通路对于多种哺乳动物组织的形成至关重要。特别是，Notch 信号传导调节增殖、细胞形状变化、分化和干细胞维持。由于Notch信号在发育过程中广泛使用，大多数Notch途径基因的小鼠突变已经产生。有趣的是，Notch1-/-、Notch2-/- 和 Jagged1 突变小鼠均具有产前眼睛表型，但人们对这些基因在早期眼睛中的作用知之甚少。此外，Notch 配体 Jagged1 的显性人类突变会导致 Alagille 综合征，其中一些患者表现出先天性前眼畸形。我们已经证明Notch效应器Hes1是小鼠晶状体细胞增殖所必需的，并且Hes1:Pax6双突变小鼠是无眼的。这些发现促使我们更好地了解 Notch 信号在早期眼睛发育过程中的作用，特别是晶状体形成过程中。使用靶向缺失小鼠（完全突变和条件等位基因）的组合，我们建议确定a）晶状体和视囊生长和形态发生过程中Notch信号传导的要求，b）Notch配体Jagged1在晶状体形成过程中的作用以及c）Notch信号传导和Pax6在晶状体形成过程中如何相互作用。所有研究都将采用条件 (cre-lox) 小鼠品系、组织学、免疫组织化学、原位杂交、小鼠胚胎学和 PCR 基因分型。这些研究将为生长和形态发生过程提供新信息，这对所有后生动物的发育至关重要。我们预计这些研究将更好地了解 Alagille 无虹膜综合征、Peter 氏畸形、小眼症和无眼症。这里的研究结果也将广泛用于癌症生物学领域，因为过量激活的 Notch1、Hes1 或 Jagged1 表达发生在多种人类肿瘤中。 这项研究的目的是利用小鼠模型了解哺乳动物晶状体形成的潜在分子机制。我们建议通过研究晶状体形成的哪些方面需要Notch细胞间信号通路来做到这一点。在身体的其他部位，Notch 信号传导控制细胞形状的变化、生长和死亡。由于这些原因，Notch 通路的突变可能导致癌症。此前尚未全面了解缺口在镜头中的作用方式、时间和位置。这些研究将有助于更好地了解晶状体如何形成，并有助于更好地设计晶状体白内障和阿拉吉尔综合征的疾病疗法。