Regulaton of Urothelial Growth

描述（由申请人提供）：整个下尿路的管腔表面，包括肾盂、输尿管、膀胱和近端尿道，被标准教科书中描述为移行上皮或尿路上皮的细胞类型所覆盖，其特征是高度特化的顶端细胞表面覆盖着坚硬的尿路上皮斑块，这些斑块由六边形堆积的16纳米尿路颗粒组成。有人认为，尿路上皮缺陷可导致渗透性屏障功能的丧失，从而使一些尿液刺激物渗透到膀胱壁上，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的尿路上皮细胞。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起源，并且有迹象表明尿路上皮具有生物化学异质性。在这个项目中，我们将(i)通过分析内在差异和外在调节对尿路上皮表型的相对贡献，确定覆盖肾盂、输尿管、膀胱和尿道近端的尿路上皮是否实际上由几种不同的细胞系组成，以及（ii）使用细胞动力学、细胞培养和干细胞移植技术鉴定不同尿路上皮室中的干细胞。这些拟议的研究可以提供重要的信息，因为如果尿路上皮确实可以分为属于不同细胞系的几个不同的亚群，人们需要重新检查一些早期研究的有效性，在这些研究中，来自尿路不同部位的尿路上皮细胞被交替使用。由于干细胞是致癌物、基因治疗的首选靶点，而且它们特别适合于组织工程和组织重建，我们的研究可以对尿路各部分组织工程的尿路上皮细胞来源、膀胱手术切除后尿路上皮伤口愈合的细胞来源、尿路上皮细胞可能参与间质性膀胱炎和细菌的部位特异性变异：尿路上皮相互作用和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.