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

基本信息

批准号：
7579777
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
项目类别：
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/7579777
关键词：
Address Affect Alagille Syndrome Alleles Animals Aniridia Anophthalmos Anterior Arts Binding Biochemical Body part 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 Outcome Pathway interactions Patients Pattern Phenotype Process Rana Regulation Role Shapes Signal Pathway Signal Transduction Stem cells Structure Technology Testing Tissues design eye formation fly in vivo intercellular communication jagged1 protein lens lens morphogenesis member mouse development mouse model mutant notch protein optic cup prenatal protein protein interaction receptor research study skeletal tumor

项目摘要

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）：该提案使用小鼠模型研究了人眼疾病的根本原因。我们专注于Notch信号通路，这对于形成多个哺乳动物组织是至关重要的。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信号在开发过程中广泛使用，因此已经创建了大多数Notch途径基因中的小鼠突变。有趣的是，Notch1 - / - ，Notch2 - / - 和Jagged1突变小鼠每个都具有产前眼科表型，但是对这些基因的早期眼睛的作用知之甚少。另外，凹槽配体jagged1中的主要人类突变会导致阿拉吉综合征，其中一些患者表现出先天性的前眼畸形。我们已经表明，小鼠透镜细胞增殖需要Notch效应子HES1，而Hes1：PAX6双突变小鼠是性的。这些发现激发了我们在早期眼部发育中更好地理解Notch信号的作用，尤其是晶状体的形成。使用靶向缺失小鼠（完全突变体和条件等位基因）的组合，我们建议a）a）在晶状体和视囊生长和形态发生过程中凹口信号的需求，b）Notch配体jagged1在晶状体形成过程中的作用，以及c）在LENS形成过程中如何相互作用。所有研究将采用条件（CRE-LOX）小鼠菌株，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的过程提供新的信息，这是所有后生动物发展的基础。我们预计，这些研究将对阿拉吉综合症，彼得的异常，微观心血管和性心血管症有更好的了解，因为过量激活的Notch1，Hes1或Jagged1表达出现在各种人类肿瘤中。这项研究的目的是了解使用小鼠模型的哺乳动物晶状体如何形成的基本分子机制。我们建议通过研究晶状体形成的哪些方面需要Notch细胞到细胞信号通路来做到这一点。在身体的其他部位，Notch信号控制细胞形状的变化，生长和死亡。由于这些原因，缺口途径中的突变会导致癌症。以前尚未解决透视在镜头中如何，何时何地在镜头中的彻底理解。这些研究将更好地了解晶状体如何形成晶状体疾病疗法和阿拉吉尔综合征的更好设计。