Beta1 integrin and renal tubulogenesis

描述(申请人提供)：整合素是跨膜异二聚体1和2亚单位糖蛋白，介导细胞和细胞外基质(ECM)之间的相互作用。在人类中，有181和82亚基，它们以受限的方式结合形成二聚体，每个亚基都表现出不同的配体结合性质。整合素在器官发育和形态发生中起关键作用，因为它们调节细胞的形状、极性、生长和运动。21是肾脏中表达最丰富的整合素亚基，可与至少121个亚基结合。其短的细胞质尾巴与许多细胞质分子结合，这些分子对整合素介导的信号转导和细胞骨架的调节至关重要。虽然21整合素是正常胚胎发育所必需的，但其在肾脏发育中的特殊功能尚不清楚。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)分析这种受体在肾脏发育中的作用。最近获得的FLOX21整合素小鼠和由肾单位节段特异性启动子驱动的Cre重组酶小鼠现在可以确定21整合素在特定肾单位节段的发育和/或功能中的作用。此外，利用产生点突变敲入小鼠的能力，有可能确定整合素细胞质尾巴在体内器官发育和/或功能中的作用。肾脏的收集系统来源于输尿管芽(UB)，它在早期发育过程中经历重复的双裂分支事件，随后是肾小管的生长、伸长和分化阶段。通过将21缺失和敲入小鼠与在UB发育开始时表达cre的小鼠(Hoxb7cre)或在大多数分支形态发生之后表达cre的小鼠(Aquaporin2cre)杂交，我们将检验这一假设，即21整合素对Ub分支形态发生至关重要，但对于集合管的生长、延长和分化是必需的。目的1)研究UB中整合素21缺失对肾脏发育和功能的影响。目的2)确定21整合素胞浆尾巴在肾集合系统发育中的作用。目的3)探讨整合素21诱导肾上皮细胞分化和分支形态形成的机制及其意义。这项拨款申请中提出的研究将提供对正常肾脏发育机制的洞察。此外，他们还将调查儿童肾脏收集系统异常的机制，这是儿科人群终末期肾功能衰竭的常见原因。

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.