MOLECULAR EVENTS IN UROGENITAL DEVELOPMENT

当输尿管芽侵入肾脏时，肾脏开始发育。 后肾间充质并诱导其转变为上皮样细胞 表型。诱导的间充质然后诱导输尿管芽 布兰奇。这种互惠的诱导是由一系列已知和 我们怀疑还有更多未知分子。我们节目的主要目的是 以确定在这一过程中至关重要的新分子。 PPG的成员已经确定了关键的新基因 肾发生与c-ret癌基因及其配体GDNF的关系 基因缺失后，会发展成肾脏发育不全。同样的小组，由康斯坦蒂尼博士领导 发现了一种名为Axin的新基因的突变，这是融合的产物 小鼠的基因座也会导致严重的肾脏发育不良，以及许多兴奋 当他们发现这种基因是一种关键的 WNT途径的组成部分，该途径被认为是 泌尿生殖系统发育。PPG的其他成员最近进行的一项研究 (Mendelsohn)发现一种维甲酸受体(RARβ2)是 在基质细胞中高表达，该基因的缺失导致 肾发育不全。J·巴拉施博士培育出一种输尿管芽细胞系 谁的培养上清液能使间充质细胞免于凋亡？ 膜诱导被挽救的间充质转化为管状上皮。 他已经从这些上清液中提纯了生长因子 产生了针对诱导的抑制性单抗 膜。Al-Awqati博士产生了一种能抑制 分枝形态发生，并提纯了其抗原，一种膜蛋白 在诱导的间质中表达，但在成人肾脏中不表达。CDNA3 表明这是一种新的基础蛋白，很可能是另一种蛋白的受体 细胞外基质中的蛋白质。另一种抗体被抑制 发育中肾脏的血管生成及其抗原提纯的研究 克隆后，发现该基因在系膜和平滑肌中均有表达 成虫体内的细胞。 这四位具有互补专业知识的科学家将通过 利用遗传学、生物化学和细胞学方法对结构进行检测 以及这些新基因的功能和它们在人类免疫缺陷形成中的作用 肾脏的三维结构。虽然很明显， 先天性肾发育不良一定是由这些基因和基因突变引起的 其他形态发生基因，有证据表明基因决定了 起作用的肾单位数量的差异可能是核心原因 很多种高血压，也许还有其他肾脏疾病。因此， 肾脏发育早期的研究，即肾脏发育的早期 肾单位的数量被确定可能具有广泛的临床意义。 这意味着什么。

Development of the kidney begins when the ureteric bud invades the metanephric mesenchyme and induces it to change to an epithelial phenotype. The induced mesenchyme then induces the ureteric bud to branch. This reciprocal induction is mediated by a cascade of known and we suspect many more unknown molecules. The major aim of our Program is to identify new molecules that are critical in this process. Members of this PPG have already identified new genes that are critical nephrogenesis, the c-ret oncogene and its ligand GDNF; when either is deleted, renal agenesis develops. The same group, led by Dr. Constantini found that mutation in a new gene termed Axin, the product of the fused locus in mice also leads to severe kidney dysplasia, and much excitement was generated when they discovered that this gene is a critical component of the wnt pathway, a pathway known to be critical for urogenital development. A recent study by another members of this PPG (Mendelsohn) found that one retinoic acid receptor (RAR beta 2) is highly expressed in the stromal cells and deletion of this gene leads to renal agenesis. Dr. J Barasch has produced a ureteric bud cell line whose supernatant can rescue mesenchyme from apoptosis and whose membrane induce the rescued mesenchyme to covert to tubular epithelia. He has already purified growth factors from these supernatants and generated inhibitory monoclonal antibodies against the inducing membranes. Dr. Al-Awqati generated a monoclonal antibody that inhibited branching morphogenesis and has purified its antigen, a membrane protein expressed in induced mesenchyme but not in the adult kidney. The cDNA shows that is a new basal protein likely to be a receptor for another protein in the extracellular matrix. Another antibody inhibited angiogenesis in the developing kidney and when its antigen was purified and cloned, it was found to be expressed in mesangial and smooth muscle cells in the adult. These four scientists with complementary expertise will collaborate by using genetic, biochemical and cellular method to examine the structure and function of these new genes and their role in the formation of the three dimensional architecture of the kidney. While it is obvious that congenital renal dysplasias must be caused by mutations in these and other morphogenetic genes, there is evidence that genetically determined differences in the number of functioning nephrons might be at the heart of many kinds of hypertension and perhaps other kidney diseases. Hence, studies of the early stages of kidney development, the stage at which the number of nephrons is determined are likely to have wide clinical implications.