ErbB3 Receptor and Renal Development

描述：(申请人提供)肾脏发育在以下情况下启动 输尿管芽与后肾胚泡接触并生长。 这启动了一系列相互感应的相互作用 刺激：a)输尿管芽逐渐分枝；b)转换和 胚泡细胞向肾小管上皮细胞分化的研究 肾单位结构平行形成。这些事件导致 最终形成复杂的结构，即成熟的肾脏。 一些生长因子/受体对已被证明可以调节胚胎 肾脏发育，但更多的调节因素仍有待确定。一个角色 对于表皮生长因子受体，是erbB受体家族的成员 目前还不清楚这一过程中的情况。根据初步数据，我们 假设erbB3受体及其配体NeuRegin发挥重要作用 在胎儿肾脏发育中的作用。为了检验这一假设，两组 实验将以小鼠作为模型发育系统进行。 首先，ErbB3受体和NeuRegin在卵巢癌中的表达模式 发育中的肾脏将通过免疫组织化学和分子生物学来确定 生物技术。如果这个受体/配体对调节胎儿肾脏 开发，则必须在适当的时间表达这两个组件 在肾脏中的位置发挥作用。此外，我们还将继续 初步结果表明，另一种神经调节蛋白受体ERBB4是 在发育中的肾脏中未在适当的时间和地点表达 调节肾脏发育。第二，erbB3的操控效果 体内和体外胎儿肾脏发育的受体活性将是 通过比较野生型和erbB3在体内的肾脏发育来阐明 基因敲除小鼠及通过检测NeuRegin处理对胎儿的影响 野生型胎鼠肾脏的发育及erbB3基因敲除 用胎肾器官培养系统培养胎鼠肾脏。参数设置为 包括胚泡介导的进行性分枝 输尿管芽、肾发生(由多个肾小球定义) 输尿管芽介导的后肾胚泡细胞的诱导(通过检查 诱导胚泡细胞的几个标志物的表达)。这些研究将 明确确定erbB3受体的活性：1)是否会影响 胎儿肾脏发育；和2)正常胎儿肾脏所必需的 发展。

DESCRIPTION: (Provided by Applicant) Kidney development is initiated when the ureteric bud comes in contact with and grows into the metanephric blastema. This sets in motion a series of reciprocal inductive interactions which stimulate: a) a progressive branching of the ureteric bud; b) conversion and differentiation of the blastemal cells into renal tubular epithelial cells with parallel formation of the nephron structure. These events lead ultimately to formation of the complex structure which is the mature kidney. Several growth factor/receptor pairs have been shown to modulate embryonic kidney development, but many more modulators remain to be identified. A role for epidermal growth factor receptor, a member of the family of erbB receptors in this process is currently unclear. Based on preliminary data we hypothesize that erbB3 receptor and its ligand, neuregulin, play important roles in fetal renal development. To test this hypothesis, two sets of experiments will be performed using the mouse as a model developmental system. First, the expression patterns for erbB3 receptor and neuregulin in the developing kidney will be defined using immunohistochemical and molecular biological techniques. If this receptor/ligand pair modulates fetal renal development, then both components must be expressed at appropriate times and places in the kidney to exert an effect. In addition, we will pursue preliminary results suggesting that erbB4, the other neuregulin receptor, is not expressed in the developing kidney at an appropriate time and place to regulate kidney development. Second, the effect of manipulation of erbB3 receptor activity on fetal renal development both in vivo and in vitro will be elucidated by comparing kidney development in vivo in wild type versus erbB3 knockout mice and by examining the effect of neuregulin treatment on fetal renal development of both wild type fetal mouse kidneys and erbB3 knockout fetal mouse kidneys using a fetal kidney organ culture system. Parameters to be examined include the blastema-mediated progressive branching of the ureteric bud, nephrogenesis (as defined by a number of glomeruli), and ureteric bud-mediated induction of metanephric blastemal cells (by examining expression of several markers of induced blastemal cells). These studies will determine unambiguously whether erbB3 receptor activity: 1) can influence fetal renal development; and 2) is required for normal fetal renal development.