ErbB3 Receptor and Renal Development

描述：（由申请人提供）肾脏发育开始时， 输尿管芽与后肾芽基接触并生长于后肾芽基内。 这就启动了一系列相互的感应作用， 刺激：a）输尿管芽的渐进分支; B）转化和 胚基细胞向肾小管上皮细胞的分化 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。 几种生长因子/受体对已被证明可以调节胚胎发育。 肾脏发育，但更多的调节剂仍有待确定。 了作用 表皮生长因子受体，erbB受体家族成员 在这个过程中，目前还不清楚。 根据初步数据，我们 假设erbB 3受体及其配体神经调节蛋白在 在胎儿肾脏发育中的作用。 为了验证这一假设， 将使用小鼠作为模型发育系统进行实验。 第一，erbB 3受体和神经调节蛋白在神经胶质瘤中的表达模式。 发育中的肾脏将使用免疫组织化学和分子生物学来定义。 生物技术 如果这种受体/配体对调节胎儿肾 发展，那么这两个组成部分必须在适当的时候表达， 在肾脏中发挥作用。 此外，我们将继续 初步结果表明，erbB 4，另一种神经调节蛋白受体， 在适当的时间和地点， 调节肾脏发育。 二、erbB 3的操纵效果 受体活性在体内和体外对胎儿肾发育的影响将是 通过比较野生型与erbB 3的体内肾脏发育来阐明 基因敲除小鼠，并通过检查neuregulin治疗对胎儿的影响， 野生型和erbB 3基因敲除小鼠胚胎肾脏的发育 使用胎肾器官培养系统的胎鼠肾。 参数以 包括芽细胞介导的进行性分支的研究。 输尿管芽，肾发生（由肾小球数量定义），以及 输尿管芽介导的后肾胚基细胞的诱导（通过检查 诱导胚基细胞的几种标记物的表达）。 这些研究将 明确确定erbB 3受体活性是否：1）可以影响 胎儿肾脏发育; 2）正常胎儿肾脏发育所需 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.