EPITHELIAL/MESENCHYMAL TRANSFORMATION IN EYE DEVELOPMENT

眼睛发育中的上皮/间质转化

基本信息

批准号：
6179819
负责人：
ELIZABETH D HAY
金额：
$ 30.97万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2003-01-31
项目状态：
已结题

项目摘要

The broad objective of this application is to understand the tissue transitions that underlie the embryonic development of the anterior eye, including the role that these transformations play in eye pathologies as well as in normal morphogenesis. The objectives of the present proposal are to decipher the molecular mechanisms that underlie transformation of epithelium to mesenchyme (EMT) and mesenchyme to epithelium (MET) and to explain the physiological mechanism used by the meesenchymal cell to invade and migrate through the matrix. Epithelium is the primitive tissue type, residing on top of extracellular matrix (ECM) as a continuous sheet of adherent cells. Creation of the mesenchymal cell adds complexity to body form, permitting the ECM between epithelia to be inhabited by inwandering cells that diversify ECM composition and migrate great distances, e.g., from neural tube to the cornea of the eye in the case of neural creast. However, inappropriate transformation of epithelium to mesenchyme in the adult can bring about abnormal ECM deposition, as in anterior capsular cataract, and devastating ECM invasion, as in malignant metastasis. The Specific aims are to study: (1) cellular mechanisms of corneal and uveal mesenchymal cell migration into and through ECM, using the new confocal microscope to view living cells labeled with sophistcated cytoskeletal probes; we believe ours is the first study to address motility mechanisms in malignant choroid melanoma cells and that new insights will be gained about motility in metastasis; (2) molecular mechanisms of the transformation of lens to mesenchyme induced by suspension in collagen gel; this study focuses on the role of signal tranduction initiated by the protoncogene, c-src and the master mesenchymal genes thus activated in the induction of EMT; (3) induction of MET in corneal fibroblasts and choroid meanoma cells; the fibroblasts and malignant melanoma "mesenchyme" will be transfected with genes for E-cadherin and/or N-Cadherin. MET inducing agents (e.g., Wnt-1 protein) are added in some cases. The results of this study could nominate cadherin-induced MET as a possible way of inhibiting uveal metastasis in vivo.

该应用的广泛目的是了解组织过渡是前部胚胎发育的基础眼睛，包括这些转变在眼中扮演的角色病理以及正常形态发生。目标的目标目前的建议是破译分子机制上皮转化为间质（EMT）和间质上皮（Met）并解释生理 Meesprimal细胞使用的机制侵入和迁移通过矩阵。上皮是原始的组织类型，位于细胞外基质（ECM）的顶部作为连续的粘附板细胞。间充质细胞的创建增加了身体形式的复杂性，允许上皮之间的ECM居住在inwandering ECM组成和迁移较大距离的细胞，例如从神经管到眼睛的角膜。但是，上皮向间充质的不当转化在成年人中可以带来异常的ECM沉积，例如前部囊囊白内障和毁灭性的ECM入侵，如恶性转移。具体目的是研究：（1）角膜和角膜和卵子间充质细胞使用ECM迁移和通过ECM迁移新的共聚焦显微镜查看用复杂呈现的活细胞细胞骨架探针；我们认为我们的研究是第一个解决的研究恶性脉络膜黑色素瘤细胞中的运动机制，关于转移运动的运动能力将获得新的见解；（2）分子晶状体转化向间充质的机制在胶原蛋白凝胶中悬浮；这项研究重点是信号的作用由质子生物，C-SRC和主人发起的转盘因此，在EMT诱导中激活了间充质基因；（3）在角膜成纤维细胞和脉络膜均匀细胞中诱导Met；成纤维细胞和恶性黑色素瘤“间充质”将是用E-钙粘蛋白和/或N-钙粘着蛋白转染的基因。见面在某些情况下，添加了诱导剂（例如Wnt-1蛋白）。这这项研究的结果可以提名为cadherin诱导的MET 在体内抑制紫美转移的可能方法。