Regulaton of Urothelial Growth

描述（由申请人提供）：整个下尿路（包括肾盂、输尿管、膀胱和近端尿道）的腔表面衬有标准教科书中描述为移行上皮或尿路上皮的细胞类型，其特征在于高度特化的顶端细胞表面被由六边形堆积的16 nm尿斑蛋白颗粒组成的刚性尿路上皮斑块覆盖。已经表明，尿路上皮缺陷可导致渗透屏障功能丧失，从而允许一些尿液刺激物渗透到膀胱壁中，从而引起间质性膀胱炎的疼痛。此外，一般认为，尿路不同部位的尿路上皮细胞是相同的，因此研究一个区域的细胞得出的结论应该适用于所有尿路上皮细胞。然而，已知肾盂/输尿管/三角区的尿路上皮细胞与其他部位的尿路上皮细胞具有不同的胚胎学起源，并且有迹象表明尿路上皮细胞具有生物化学异质性。在这个项目中，我们将（i）通过分析内在分化与外在调节对尿路上皮表型的相对贡献来确定覆盖肾盂、输尿管、膀胱和近端尿道的尿路上皮是否实际上由几种不同的细胞谱系组成，以及（ii）使用细胞动力学、细胞培养和干细胞移植技术来鉴定各种尿路上皮隔室中的干细胞。这些拟议的研究可以产生重要的信息，因为如果尿路上皮细胞确实可以分为几个不同的亚群属于不同的细胞谱系，一个需要重新检查的有效性，一些早期的研究中，尿路上皮细胞从不同部位的尿路可互换使用。由于干细胞是致癌物、基因治疗的优选靶点，并且它们特别适合于组织工程和组织重建，因此我们的研究可以对用于泌尿道各部分的组织工程的尿路上皮细胞的来源、手术切除膀胱后体内尿路上皮伤口愈合的细胞来源、间质性膀胱炎中尿路上皮细胞的可能参与和细菌：尿路上皮相互作用中的位点特异性变化，以及各种尿路上皮肿瘤的细胞起源。

DESCRIPTION (provided by applicant): The luminal surface of the entire lower urinary tract including renal pelvis, ureter, bladder and proximal urethra is lined by a cell type described in standard textbooks as the transitional epithelium or urothelium, which is characterized by a highly specialized apical cell surface covered by rigid-looking urothelial plaques consisting of hexagonally packed 16 nm uroplakin particles. It has been suggested that urothelial defects can result in a loss of the permeability barrier function allowing the penetration of some urine irritants into the bladder wall thus causing pain in interstitial cystitis. In addition, it is generally assumed that urothelial cells lining the different portions of the urinary tract are the same; hence conclusions derived from studying cells of one region should be applicable to all urothelial cells. However, urothelia of renal pelvis/ureter/trigone are known to have a different embryological origin than urothelial cells of other sites, and there are indications that urothelium is biochemically heterogeneous. In this project, we will (i) determine whether the urothelia that cover renal pelvis, ureter, bladder, and proximal urethra actually consist of several distinct cell lineages by analyzing the relative contributions of intrinsic divergence vs. extrinsic modulation to urothelial phenotypes, and (ii) identify the stem cells in various urothelial compartments using cell kinetic, cell culture and stem cell transplantation techniques. These proposed studies can yield important information because if urothelium indeed can be separated into several distinct subpopulations belonging to different cell lineages, one needs to re-examine the validity of some earlier studies in which urothelial cells from different parts of the urinary tract were used interchangeably. Since stem cells are the preferred targets of carcinogens, gene therapy, and they are particularly suited for tissue engineering and tissue reconstitution, our studies can have practical implications on the source of urothelial cells for tissue engineering of various parts of the urinary tract, the cellular origin of in vivo urothelial wound healing following the surgical removal of the bladder, the possible involvement of urothelial cells in interstitial cystitis and in site-specific variations in bacterium: urothelium interactions, and the cellular origin of various urothelial tumors.