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

基本信息

批准号：
10084294
负责人：
Santhakumar Manicassamy
金额：
$ 33.88万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10084294
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&apos 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

项目摘要

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 4-23% 会出现肾脏表现或泌尿道并发症 (CD) 和溃疡性结肠炎 (UC)（炎症性肠病，IBD），通常发生在患有严重、长期预防和治疗 IBD 和相关的急性肾损伤 (AKI) 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。需要了解结肠炎介导的 AKI 的免疫学机制，这将指导识别新的我们已经确定了预防或治疗 IBD 和 IBD 相关 AKI 的新目标。经典 Wnt 通路作为调节串扰的关键分子通路，之前未被怀疑过其作用我们发现，在疾病进展过程中，肠道和肾脏之间的 Wnt 配体通过低信号传导。肾抗原呈递细胞 (APC) 中的密度脂蛋白受体相关蛋白 5 和 6 (LRP5/6) 至关重要用于抑制肾脏病理性炎症反应和结肠炎介导的 AKI 消融。小鼠 DC 或 MP 中的受体会导致免疫稳态丧失并增强结肠炎介导的 AKI。然而，LRP5/6 在肾脏 APC 中发挥作用的下游机制可抑制炎症和 AKI 目前提案的具体目标是（目标 1）了解规范是如何实现的。 Wnt 赋予肾 APC 通路调节表型并抑制结肠炎介导的 AKI (Aim2)；了解肾 APC 如何响应经典 Wnt 信号传导而产生 IL-10 和视黄酸抑制肾脏的氧化应激和结肠炎介导的 AKI，并且（目标 3）检查“证据” 概念”，经典 Wnt 通路的药理学激活可预防肾脏炎症和结肠炎 - 所提出的研究的成功完成将显着增强我们的理解。重要的是，经典 Wnt 控制肠道炎症反应的机制。拟议的研究将为增强 Wnt 信号传导的抗炎反应提供新途径，同时抑制病理性炎症反应，可能对治疗 IBD 具有显着的治疗作用相关的 AKI 和其他免疫介导的肾脏疾病。