Injury Response Mediated Pathogenesis in Renal Ciliopathies

损伤反应介导的肾纤毛病发病机制

• 批准号: 10571152
• 负责人: Bradley K. Yoder
• 金额: $ 52.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571152
• 关键词: Acceleration; Adult; Affect; Alleles; Area; Automobile Driving; Cells; Cilia; Cisplatin; Clinical; Cyst; Cystic Kidney Diseases; Cystic kidney; Data; Defect; Development; Disease Progression; Epithelial Cells; Epithelium; Erinaceidae; Functional disorder; Gene Expression Profile; Genes; Genetic Epistasis; Genetic Transcription; Goals; Immune; Inflammatory Response; Injury; Injury to Kidney; Ischemia; Kidney; Lead; Location; Mediating; Molecular; Mus; Mutant Strains Mice; Mutation; Nature; Nephrons; PKD2 protein; Pathogenesis; Pathology; Pathway interactions; Phenotype; Predisposition; Process; Proteins; Renal function; Renal tubule structure; Reperfusion Therapy; Repression; Resolution; Sensory; Series; Severities; Signal Pathway; Signal Transduction; Testing; Tissues; aged; cell injury; ciliopathy; conditional mutant; epithelial injury; experience; injury and repair; mutant; novel; novel strategies; protein function; renal epithelium; repaired; response; response to injury; smoothened signaling pathway; tissue repair; treatment strategy

PROJECT SUMMARY/ABSTRACT Primary cilia are present on most renal epithelial cells and their disruption leads to cyst formation. Despite their clinical importance, the function of the primary renal cilium remains poorly understood. In previous studies, we and others demonstrated that when cilia assembly (Ift88 mutant) or function (Pkd1 or Pkd2) is disrupted in adult mice, cysts form slowly in focal areas. This occurs despite nearly all epithelial cells in the kidney being mutant for these genes. A hint as to why these cysts develop in focal locations in the adult-induced mutants has emerged from data indicating that renal injury promotes cyst formation and results in cyst formation throughout the kidney. Based on these data, we propose that PKD2 and cilia regulate renal injury and repair responses and that the focal cysts in the adult-induced mutants result from a few cells that have experienced an injury. In the absence of normal cilia function, these cells enter a state of persistent maladaptive repair (as marked by persistent SOX9 expression) and progress to cystogenesis. While cysts are formed in Ift88 and Pkd2 mutants, the cystic kidney phenotype is always more severe with loss of Pkd2. In double mutants, however, the cystic pathology resembles the milder Ift88 mutant alone. Our analysis further shows that the inflammatory response following injury in the Ift88 and Pkd2 mutant mice is altered and as observed with cyst formation; it is exacerbated in Pkd2 mutants compared to Ift88 or Ift88/Pkd2 double mutants. Collectively, these data suggest that IFT88/cilia and PKD2 regulate signaling activities between the ciliated tubule epithelium and the responding non-ciliated immune cells for initiation and resolution of an injury response and that cyst formation is promoted when these signaling pathways are incorrectly controlled. The goals of this proposal are to define the cellular and then molecular mechanism(s) responsible for the focal and widespread injury-induced cyst formation and how IFT88/cilia and PKD2 are involved in this process. From this proposal, we will determine whether cilia loss/dysfunction alters the kidney's sensitivity to injury and results in an increase in the state of epithelial cell maladaptive repair. We will utilize lineage tracing approaches to determine if descendants of injured cells contribute directly to cyst formation. We will define new IFT88/cilia and PKD2-dependent intercellular signaling networks involved in the injury and repair process and how they are dysregulated when cilia are disrupted (Ift88 mutant) or cilia function is perturbed (Pkd2 mutant). Finally, we will define mechanisms by which loss of Ift88 in a Pkd2 mutant background suppresses cyst severity through changes in these injury and repair signaling pathways. The data from the proposal are needed to: 1) elucidate novel functions of the renal cilium, 2) define cellular mechanisms involved in formation of the sporadic and widespread cysts, 3) understand how IFT88/cilia and PKD2 are involved in regulating injury/repair responses, 4) assess how disrupting this injury response promotes cyst formation and expansion, and 5) explore mechanisms involved in the epistatic relationship between Ift88 and Pkd2 mutations.

项目摘要/摘要 在大多数肾上皮细胞上存在原发性纤毛，它们的破坏会导致囊肿形成。尽管他们 临床重要性，主要的肾纤毛的功能仍然很少理解。在以前的研究中，我们 其他人则证明，当成人中纤毛组装（IFT88突变体）或功能（PKD1或PKD2）时 小鼠，囊肿在焦点区域缓慢形成。尽管肾脏中几乎所有上皮细胞都是突变体 对于这些基因。关于这些囊肿在成人引起的突变体中的焦点位置发生的原因的暗示 从数据表明肾脏损伤会促进囊肿的形成，并在整个肾脏中导致囊肿形成。 基于这些数据，我们建议PKD2和CILIA调节肾脏损伤和修复反应，并且是 成人引起的突变体中的局灶性囊肿是由于一些遭受损伤的细胞而导致的。在缺席的情况下 这些细胞的正常纤毛功能，进入持续不良适应性修复状态（如持续的SOX9所示 表达）和囊肿发生。在IFT88和PKD2突变体中形成囊肿时，囊性肾脏 随着PKD2的损失，表型总是更加严重。但是，在双突变体中，囊性病理类似于 较温和的IFT88突变体。我们的分析进一步表明，受伤后的炎症反应 IFT88和PKD2突变小鼠被改变并随囊肿形成所观察到。它在PKD2突变体中加重 与IFT88或IFT88/PKD2双突变体相比。总的来说，这些数据表明IFT88/CILIA和PKD2 调节纤毛小管上皮和反应的非裂解的免疫细胞之间的信号传导活性 为了启动和解决损伤反应，并在这些信号传导时促进囊肿的形成 途径是错误控制的。该建议的目标是定义细胞，然后分子 负责局灶性和广泛损伤引起的囊肿形成以及IFT88/纤毛和如何的机制 PKD2参与了此过程。根据该提案，我们将确定纤毛损失/功能障碍是否改变了 肾脏对损伤的敏感性，并导致上皮细胞不良修复状态的升高。我们将 利用谱系追踪方法来确定受伤细胞的后代是否直接促进囊肿形成。 我们将定义新的IFT88/CILIA和PKD2依赖性的细胞间信号网络，涉及损伤和 维修过程以及纤毛中断（IFT88突变体）或纤毛功能时如何失调 （PKD2突变体）。最后，我们将定义在PKD2突变体背景下损失IFT88的机制 通过这些伤害和修复信号通路的变化来抑制囊肿的严重程度。来自 需要：1）阐明肾纤毛的新功能，2）定义涉及的细胞机制 在零星和广泛的囊肿的形成中，3）了解IFT88/Cilia和PKD2如何参与 调节伤害/维修反应，4）评估这种伤害反应如何促进囊肿的形成和 膨胀和5）探索与IFT88和PKD2突变之间上皮关系的机制。