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：克罗恩病患者的肾脏表现或尿并发症发生在4-23％（CD）和溃疡性结肠炎（UC）（炎症性肠病的形式，IBD），通常在严重，长期的患者中常规疾病。预防和治疗IBD和相关的急性肾脏损伤（AKI）很重要临床问题，但热免疫干预的分子靶标仍然难以捉摸。有关键需要理解结肠炎介导的AKI的免疫机制，这将指导确定新的预防或治疗IBD和IBD相关的AKI的目标。我们已经确定了一个新的在调节性交叉言论中，典型的Wnt途径的先前未刺激作用是一个关键的分子途径在疾病进展过程中肠道和肾脏之间。我们表明，通过低 - 发出信号的Wnt配体肾脏抗原呈递细胞（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和结肠炎介导的AKI的病理炎症反应。这些共同的消融小鼠DC或MPS中的受体会导致免疫稳态丧失，并增强结肠炎介导的AKI。但是，LRP5/6在肾APC中起作用以抑制注射和AKI的下游机制完全未知。当前建议中的具体目标是（目标1）了解规范如何 WNT途径在肾脏APC上授予调节表型并抑制结肠炎介导的AKI；（AIM2）了解肾脏APC产生的IL-10和视黄酸是如何响应规范Wnt信号的抑制肾脏和结肠炎介导的AKI中的氧化应激，（AIM3）检查“证明概念”规范WNT途径的药理激活可防止肾脏感染和结肠炎介导的Aki。拟议研究的成功完成将大大增强我们的理解规范WNT控制肠中炎症反应的机制。重要的是，拟议的研究将提供新的途径，以增强Wnt信号的抗炎反应，同时抑制病理炎症反应，可能在治疗IBD- 相关的AKI和其他免疫介导的肾脏疾病。