RETINAL RECEPTORS FOR DEVELOPMENTAL CUES

发育线索的视网膜受体

• 批准号: 2019835
• 负责人: DENNIS O CLEGG
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2019835
• 关键词: cell adhesion; cell cell interaction; cell migration; cell proliferation; chick embryo; complementary DNA; developmental neurobiology; gene expression; in situ hybridization; integrins; laboratory mouse; molecular cloning; neural fasciculation; neurogenesis; organ culture; protein structure function; retina; retinal bipolar neuron; retinal ganglion; transfection /expression vector

The development of the retina required a complex interplay between retinal cells and the external molecular and cellular cues that regulate their development. The molecular basis of cell-cell interactions in the retina is poorly understood. Insight into these interactions may lead to treatments aimed at regenerating optic nerve function after injury and to a greater understanding of retinal disease resulting from aberrant cell adhesion events. Preliminary results in this proposal describe evidence that an important cell adhesion receptor subunit, previously thought to act only in blood cells, is expressed in developing retina. The presence of this subunit, called integrin alpha 4, suggests that a novel retinal mechanism for cell-cell interactions may be in operations during retinal development. This proposal addresses the function of alpha4 integrins in retinal development. Integrins are a family of transmembrane, heterodimeric proteins that acts as receptors for a broad range of extracellular matrix and cell surface glycoproteins. In lymphocytes and leukocytes, alpha4 integrins acts as bifunctional receptors for both classes of ligand: they mediate cell attachment to a domain in fibronectin and to the vascular cell adhesion molecule VCAM-1. Since fibronectin has not been consistently detected in developing retina, alpha4 may mediate interactions with VCAM-1 or a novel ligand. The first specific aims of this proposal are to determine the range of retinal cells that express alpha4 integrins and VCAM-1. Next, experiments are proposed to define the functions of alpha4 and VCAM-1 in vitro, using function blocking antibodies to perturb cell adhesion and neurite outgrowth. Finally, in vivo experiments are proposed to alter alpha4 expression, by expressing antisense RNA, and to block alpha4 function, by introducing blocking antibodies to define the role of alpha4 integrins in retinal development.

视网膜的发展需要在 视网膜细胞以及调节的外部分子和细胞线索 他们的发展。 细胞细胞相互作用的分子基础 视网膜知之甚少。 洞悉这些互动可能会导致 旨在在受伤后旨在再生视神经功能的治疗 更了解因异常引起的视网膜疾病 细胞粘附事件。 该提案中的初步结果描述了一个重要的证据 细胞粘附受体亚基，以前认为仅作用于血液 细胞在发育的视网膜中表达。 这个亚基的存在， 称为整联蛋白α4，表明一种新型的视网膜机制 细胞 - 细胞相互作用可能是视网膜发育过程中的操作。 该提案解决了视网膜中alpha4整合素的功能 发展。 整合素是跨膜，异二聚体蛋白的家族 作为广泛细胞外基质和细胞表面的受体 糖蛋白。 在淋巴细胞和白细胞中，α4整合素充当 两类配体的双功能受体：它们介导细胞 纤连蛋白和血管细胞粘附的结构域附着 分子VCAM-1。 由于纤连蛋白尚未始终被检测到 在开发视网膜时，alpha4可能介导与VCAM-1或A的相互作用 小说配体。 该提案的第一个具体目的是确定 表达α4整联蛋白和VCAM-1的视网膜细胞范围。 接下来，提出了实验来定义alpha4和 VCAM-1在体外，使用功能阻断抗体扰动细胞的功能 粘附和神经突生长。 最后，体内实验是 提议通过表达反义RNA和到改变α4表达 通过引入阻止抗体来定义block alpha4功能 α4整联蛋白在视网膜发育中的作用。