Regulation of colitis associated with acute kidney injury by the Wnt pathway

Wnt 通路调节与急性肾损伤相关的结肠炎

• 批准号: 10320015
• 负责人: Santhakumar Manicassamy
• 金额: $ 33.88万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320015
• 关键词: Ablation; Acute Renal Failure with Renal Papillary Necrosis; Anti-Inflammatory Agents; Antigen-Presenting Cells; Biochemical; Biological Assay; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Clinical; Coculture Techniques; Colitis; Complex; Crohn' s disease; Data; Dendritic Cells; Disease; Disease Progression; Genetic; Genetic Transcription; Homeostasis; Immune; Immunologics; Immunotherapy; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury to Kidney; Interleukin-10; Intestines; Kidney; Kidney Diseases; Knock-out; Knockout Mice; LDL-Receptor Related Protein 1; Ligands; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Oxidative Stress; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Play; Prevention; Property; Publishing; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; T cell differentiation; T cell factor 4; T-Lymphocyte; TCF7L2 gene; Testing; Therapeutic; Tissues; Tretinoin; Tubular formation; Ulcerative Colitis; WNT Signaling Pathway; antigen-specific T cells; autocrine; beta catenin; conditional knockout; cytokine; in vivo; lipoprotein receptor related protein 5; macrophage; molecular targeted therapies; mouse model; novel therapeutic intervention; paracrine; prevent; programs; receptor; response; selective expression; systemic inflammatory response; tissue injury; transcription factor; urinary

Summary: Renal manifestations or urinary complications occur in 4–23% in patients with Crohn’s disease (CD) and ulcerative colitis (UC) (forms of inflammatory bowel disease, IBD), often in those with severe, long- standing disease. Prevention and treatment of IBD and associated acute kidney injury (AKI) are important clinical problems, but molecular targets for therapeutic immune intervention remain elusive. There is critical need for understanding the immunological mechanisms of colitis-mediated AKI that will guide in identifying new targets for the prevention or treatment of IBD and IBD-associated AKI. We have identified a new and previously unsuspected role for the canonical Wnt pathway as a key molecular pathway in regulating cross‐talk between the gut and kidney during disease progression. We show that Wnt ligands that signal through low- density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in renal antigen presenting cells (APCs) is critical for suppressing pathologic inflammatory response in the kidney and colitis-mediated AKI. Ablation of these co- receptors in DCs or MPs in mice causes loss of immune homeostasis and augments colitis-mediated AKI. However, downstream mechanisms by which LRP5/6 acts in renal APCs act to suppress inflammation and AKI are completely unknown. Specific aims in the current proposal are (Aim 1) to understand how the canonical Wnt pathway imparts regulatory phenotype on renal APCs and suppresses colitis-mediated AKI; (Aim2) to understand how IL-10 and retinoic acid produced by renal APCs in response to canonical Wnt signaling suppresses oxidative stress in the kidney and colitis-mediated AKI, and (Aim3) to examine the “proof of concept” that pharmacological activation of the canonical Wnt pathway prevents renal inflammation and colitis- mediated AKI. The successful completion of the proposed studies will significantly enhance our understanding of the mechanisms by which the canonical Wnt control inflammatory responses in the intestine. Importantly, the proposed studies will provide new avenues to enhance anti-inflammatory response of Wnt signaling while suppressing pathologic inflammatory response that may have significant therapeutic impact in treating IBD- associated AKI and other immune mediated-renal diseases.

摘要：克罗恩病患者中有4-23%发生肾脏表现或泌尿系统并发症 (CD)和溃疡性结肠炎（UC）（炎症性肠病，IBD的形式），通常在那些严重的，长期的， 长期病预防和治疗IBD和相关的急性肾损伤（阿基）非常重要 临床问题，但治疗性免疫干预的分子靶点仍然难以捉摸。有关键的 需要了解结肠炎介导的阿基的免疫学机制，这将指导识别新的 用于预防或治疗IBD和IBD相关阿基的靶点。我们发现了一种新的 经典Wnt通路作为调节串扰的关键分子通路的先前未被怀疑的作用 肠道和肾脏之间的相互作用我们发现Wnt配体通过低- 肾抗原呈递细胞（APC）中的密度脂蛋白受体相关蛋白5和6（LRP 5/6）是关键的 用于抑制肾脏和结肠炎介导的阿基中的病理性炎症反应。消除这些共同- 在小鼠中，DC或MP中的受体引起免疫稳态的丧失并增强结肠炎介导的阿基。 然而，LRP 5/6在肾APC中起作用的下游机制起到抑制炎症和阿基 是完全未知的。当前提案的具体目标是（目标1）了解规范如何 Wnt通路赋予肾APC调节表型并抑制结肠炎介导的阿基;（Aim 2） 了解肾APC如何响应经典Wnt信号传导产生IL-10和视黄酸 抑制肾脏中的氧化应激和结肠炎介导的阿基，以及（Aim 3）检查“ 概念”经典Wnt途径的药理学激活可预防肾脏炎症和结肠炎- 介导阿基。建议中的研究若能顺利完成，将大大提高我们对 经典Wnt控制肠道炎症反应的机制。重要的是， 这些研究将为增强Wnt信号的抗炎反应提供新的途径， 抑制病理性炎症反应，可能对治疗IBD具有显著的治疗作用， 相关的阿基和其他免疫介导的肾脏疾病。