Beta1 integrin and renal tubulogenesis

描述（由申请人提供）：整合素是介导细胞与细胞外基质（ECM）之间相互作用的跨膜异二聚体1和2亚基糖蛋白。在人类中有18个1和8个2亚基，它们以有限的方式联合收割机结合形成二聚体，每个二聚体表现出不同的配体结合特性。整合素在器官发育和形态发生中起关键作用，因为它们调节细胞形状、极性、生长和运动。21是肾脏中表达最丰富的整合素亚基，并且可以结合至少12个1亚基。它的短胞质尾区与许多胞质分子结合，这些分子对于整合素介导的信号传导和细胞骨架的调节很重要。虽然很明显，21整合素是必要的正常胚胎发育，其在肾脏发育的具体功能是很差的特点。整合素21缺失的小鼠在围着床期死亡，因此很难（如果不是不可能的话）分析这种受体在肾脏发育中的作用。最近可用的FLOXED 21整联蛋白小鼠和小鼠与CRE重组酶驱动的肾单位段特异性启动子，现在允许我们确定的作用21整联蛋白的发展和/或功能的特定肾单位段。此外，具有产生点突变敲入小鼠的能力，可以确定整合素胞质尾在体内器官发育和/或功能中的作用。肾脏的收集系统来源于输尿管芽（UB），其在早期发育期间经历重复的双歧管分支事件，随后是管状生长、伸长和分化的阶段。通过将FLOXED 21无效和基因敲入小鼠与UB发育开始时（hoxb 7 cre）或大多数分支形态发生后（水通道蛋白2 cre）表达cre的小鼠杂交，我们将检验21整合素对UB分支形态发生至关重要但对集合管生长、伸长和分化是消耗性的这一假设。目的1）确定在发展中的UB中整合素21的损失如何影响肾脏发育和功能。目的2）探讨21整合素胞质尾区在肾集合系统发育中的作用。目的3）探讨整合素21诱导肾上皮细胞极性和分支形成的机制。叙述和意义。这项资助申请中提出的研究将深入了解正常肾脏发育的机制。此外，他们将研究儿童肾脏收集系统异常的机制，这是儿科人群终末期肾衰竭的常见原因。

DESCRIPTION (provided by applicant): Integrins are transmembrane heterodimeric 1 and 2 subunit glycoproteins that mediate the interactions between cells and extracellular matrix (ECM). In humans there are 18 1 and 8 2 subunits, which combine in a restricted manner to form dimers, each of which exhibit different ligand binding properties. Integrins play a critical role in organ development and morphogenesis as they modulate cell shape, polarity, growth and motility. 21 is the most abundantly expressed integrin subunit in the kidney and can bind at least 12 1 subunits. Its short cytoplasmic tail binds to many cytoplasmic molecules that are important for integrin-mediated signaling and modulation of the cytoskeleton. Although it is clear that 21 integrin is necessary for normal embryogenesis; its specific function in renal development is poorly characterized. Integrin 21-null mice die at the peri-implantation stage, thus making difficult, if not impossible, to analyze the role of this receptor in kidney development. Recent availability of FLOXED 21 integrin mice and mice with CRE-recombinase driven by nephron segment specific promoters now allow us to determine the role of 21 integrin in the development and/or function of specific nephron segments. In addition, with the ability to generate point mutant knock-in mice, it is possible to determine the role of the integrin cytoplasmic tail in organ development and/or function in vivo. The collecting system of the kidney is derived from the ureteric bud (UB) which undergoes repetitive bifid branching events during early development followed by a phase of tubular growth, elongation and differentiation. By crossing FLOXED 21 null and knock-in mice with mice that express cre when UB development commences (hoxb7 cre) or after the majority of branching morphogenesis has occurred (aquaporin2 cre), we will test the hypothesis that 21 integrin is critical for UB branching morphogenesis but is expendable for collecting duct growth, elongation and differentiation. Aim 1) Determine how loss of integrin 21 in the developing UB affects renal development and function. Aim 2) Determine the role of the 21 integrin cytoplasmic tail in renal collecting system development. Aim 3) Determine the mechanism whereby integrin 21 induces renal epithelial cell polarity and branching morphogenesis.Narrative and significance. The studies proposed in this grant application will provide insight into the mechanisms of normal kidney development. In addition, they will investigate the mechanisms whereby children develop abnormalities of the collecting system of the kidney, which is a common cause of end stage renal failure in the pediatric population.