Molecular and Cellular Pathobiology of Stone Forming Papillae

结石形成乳头的分子和细胞病理学

• 批准号: 10246878
• 负责人: Tarek Maurice Ashkar
• 金额: $ 25.83万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246878
• 关键词: 3-Dimensional; ART protein; Achievement; Apatites; Area; Basement membrane; Basic Science; Binding Proteins; Biological Assay; Biopsy; CD44 gene; Calcium; Calcium Oxalate; Cell Adhesion Molecules; Cells; Clinical Treatment; Confocal Microscopy; Control Groups; Crystallization; Cytometry; Deposition; Disease; Distal; Distant; Duct (organ) structure; Event; Feedback; Functional disorder; Funding; Growth; Human; Hyaluronan; Image; Immune system; Inflammation; Inflammatory; Innate Immune System; Investigation; Kidney Calculi; Lasers; Lead; Learning; Leukocyte L1 Antigen Complex; Limb structure; Link; Measures; Methodology; Methods; Microdissection; Molecular; Natural Immunity; Nephrolithiasis; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Papillary; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Phenotype; Physiological; Plug-in; Process; Protein Analysis; Proteins; Proteomics; Research; Risk; Role; Signal Transduction; TLR4 gene; Testing; Thick; Thinness; Tight Junctions; Tissue imaging; Tissues; Translating; Tubular formation; Up-Regulation; Urothelium; arm; bikunin; design; fluorescence imaging; grasp; hypercalciuria; immune activation; improved; interstitial; molecular phenotype; osteopontin; oxidative damage; protein phosphatase inhibitor-2; skills; synergism; targeted treatment; tongue papilla

During the last funding cycle, the PPG made significant advances in our understanding of the mechanisms of stone formation and growth. Project 3 has made a comprehensive and essential histopathological characterization of the papillae in human stone disease, and distinguished two main phenotypes that are essential to the pathogenesis of stone disease: plaque deposition and intratubular crystal plugging. A grasp of the contribution of each of these phenotypes to the type of stone disease is essential to understand the underlying pathology, and eventually developing targeted therapies. Achieving this objective requires the performance of unprecedented, detailed, studies of the various microenvironments within the human papillae of stone forming patients. The aims in the current proposal are designed to perform such in-depth investigations of the cellular and molecular mechanisms underlying these key events, using state-of-the-art methodology and skills of the research team. The role of interstitial calcium concentration in the formation of plaque is a fundamental concept. Aim 1 will firmly establish the importance of increased interstitial calcium in the papilla on the pathogenesis of plaque. Aim 2 will investigate the role of innate immune activation in plaque formation. Key downstream effects of innate immunity, such as oxidative stress, inflammatory signaling and crystal modulator deposition will be carefully studied. This aim is expected to define with high confidence, the role of inflammation in the pathogenesis of plaque deposition in human stone disease. Aim 3 will investigate a key mechanism of how plugging disease propagates in the papilla, by determining if ducts with plugs can stimulate oxidative stress and inflammatory signaling beyond the area contiguous to plugging. This cross -talk could lead to upregulation of adhesion molecules that facilitate more plugging in neighboring ducts. Finally, Aim 4 will investigate the rarely-studied papillary urothelium, by establishing if overgrowth of new stones over plaque is preceded by dysfunction of the overlying papillary urothelium. Methods used in these investigations will include: laser micro-dissection, 3 dimensional imaging of the papillae using confocal microscopy, tissue cytometry, state-of the art protein analysis and redox proteomic assays. Combined together, and in synergy with aims from project 1 and 2, these new aims, will greatly advance our understanding of the precise mechanisms of stone formation and growth, which will hopefully translate into more effective clinical treatments for stone disease.

在上一个供资周期中，项目规划小组在我们对环境保护机制的理解方面取得了重大进展。 结石形成和生长。项目3已作出全面和必要的组织病理学 描述了人类结石病中乳头的特征，并区分了两种主要的表型， 结石病的发病机制：斑块沉积和小管内晶体堵塞。一握 这些表型中的每一种对结石病类型的贡献对于理解 潜在的病理学，并最终开发出靶向疗法。实现这一目标需要 对人类乳头内各种微环境进行前所未有的详细研究 结石形成的病人。目前提案的目的是为了进行这种深入的研究， 这些关键事件背后的细胞和分子机制的调查，使用最先进的 研究团队的方法和技能。 间质钙浓度在斑块形成中的作用是一个基本概念。目标1将 牢固地确立了乳头间质钙增加对斑块发病机制的重要性。 目的2将研究先天免疫激活在斑块形成中的作用。关键下游影响 先天免疫，如氧化应激、炎症信号传导和晶体调节剂沉积， 仔细研究。这一目标预计将以高置信度定义炎症在炎症中的作用。 人类结石病斑块沉积的发病机制。 目的3将研究堵塞疾病如何在乳头中传播的关键机制， 具有栓塞的导管可以刺激氧化应激和炎症信号传导， 堵塞这种相互作用可能导致粘附分子的上调，从而促进更多的插入 相邻的管道。最后，目标4将研究很少研究的乳头状尿道炎，通过确定是否 新结石在斑块上过度生长之前是覆盖的乳头状尿路上皮的功能障碍。 研究方法包括：激光显微解剖、乳头三维成像 使用共聚焦显微镜、组织细胞术、最先进的蛋白质分析和氧化还原蛋白质组学测定。 这些新目标结合在一起，并与项目1和项目2的目标协同作用，将大大推进我们的 了解结石形成和生长的精确机制，这将有望转化为 更有效的结石病临床治疗方法。