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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.

该应用程序的主要目标是了解组织前脑胚胎发育过程中的转变眼睛，包括这些转变在眼睛中发挥的作用病理以及正常形态发生。该计划的目标目前的建议是破译分子机制是上皮细胞向间质细胞转化 (EMT) 的基础间充质到上皮 (MET) 并解释生理学间充质细胞侵袭和迁移的机制通过矩阵。上皮是原始组织类型，位于细胞外基质 (ECM) 的顶部作为连续的粘附片细胞。间充质细胞的产生增加了身体形态的复杂性，允许上皮细胞之间的 ECM 被入侵所占据使 ECM 成分多样化并迁移很远距离的细胞，例如，在神经嵴的情况下，从神经管到眼睛的角膜。然而，上皮细胞向间充质细胞的不适当转化在成人中可能会导致异常的 ECM 沉积，如前部囊性白内障和毁灭性的 ECM 侵袭，如恶性转移。具体目标是研究：（1）角膜和角膜的细胞机制。葡萄膜间充质细胞迁移进入并通过 ECM，使用新型共聚焦显微镜可观察带有复杂标记的活细胞细胞骨架探针；我们相信我们的研究是第一个解决恶性脉络膜黑色素瘤细胞的运动机制将获得关于转移运动的新见解； (2)分子晶状体向间质转化的机制胶原凝胶悬浮液；这项研究的重点是信号的作用由原癌基因、c-src 和 master 启动的转导间充质基因在 EMT 诱导过程中被激活； (3) 在角膜成纤维细胞和脉络膜平均瘤细胞中诱导 MET；成纤维细胞和恶性黑色素瘤“间质”将用E-钙粘蛋白和/或N-钙粘蛋白基因转染。梅特在某些情况下会添加诱导剂（例如 Wnt-1 蛋白）。这这项研究的结果可以提名钙粘蛋白诱导的 MET 作为体内抑制葡萄膜转移的可能途径。