Novel role of RIPK3-dependent necroptosis pathway in lung and kidney fibrosis

RIPK3依赖性坏死性凋亡途径在肺和肾纤维化中的新作用

• 批准号: 9981806
• 负责人: MARY E CHOI
• 金额: $ 52.34万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981806
• 关键词: ATP Citrate (pro-S)-Lyase; Architecture; Attention; Biological Markers; Biosynthetic Proteins; Bleomycin; Carbon Monoxide; Cell Death; Cell physiology; Cells; Chronic Kidney Failure; Clinical; Clinical Trials; Communities; Data; Deposition; Diagnostic; Disease; Dose; Effector Cell; Epithelial Cells; Etiology; Experimental Models; Extracellular Matrix; Fatty Acids; Fibroblasts; Fibrosis; Homeostasis; Human; Inflammation; Inflammatory; Investigational Therapies; Kidney; Lower respiratory tract structure; Lung; Lung diseases; Mediating; Mediator of activation protein; Modality; Modeling; Molecular Target; Mus; Organ; Organ failure; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Phosphotransferases; Physiological; Process; Production; Protein Biosynthesis; Proteins; Publishing; Pulmonary Fibrosis; RIPK1 gene; RIPK3 gene; Regulation; Role; Safety; Severities; Severity of illness; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Testing; Therapeutic; Therapeutic Effect; Tissues; Transforming Growth Factors; Ureteral obstruction; alveolar destruction; burden of illness; candidate marker; diagnostic biomarker; expectation; fatty acid metabolism; fibrogenesis; human disease; idiopathic pulmonary fibrosis; indium-bleomycin; kidney fibrosis; macrophage; nephrogenesis; novel; organ injury; receptor function; response to injury; therapeutic target

Abstract Fibrosis is a pathogenic process in organs (e.g., lung, kidney) involving the excess deposition of extracellular matrix (ECM) leading to loss of organ homeostasis. Fibrosis is the hallmark of progressive chronic kidney diseases as a common pathogenic response to injury. Similarly, end-stage lung diseases are often characterized by lung fibrosis. Recent studies suggest that necroptosis, a genetically-programmed form of cell death that is regulated by receptor-interacting protein-1 and -3 (RIPK1, RIPK3) kinases, may have emerging significance in human disease. Little is currently known of the role of RIPK3 in the pathogenesis of organ fibrosis. We have exciting preliminary data that RIPK3 can exert crucial functions in experimental models of kidney and lung fibrosis. Intriguingly, mice deficient in RIPK3, but not in its signaling target the mixed lineage kinase domain-like protein (MLKL), were protected against kidney fibrosis. We have also identified a RIPK3-mediated signaling pathway that regulates fatty acid (FA) metabolism by activating ATP citrate lyase (ACL), and contributes to kidney fibrosis. In contrast, mice deficient in either RIPK3 or MLKL were susceptible to pulmonary fibrosis. These studies suggest that RIPK3 may represent a novel mediator of organ fibrosis with differential organ or tissue-specific effects. The endogenous gaseous molecule carbon monoxide (CO) has been implicated as an experimental therapeutic modality in organ injury. Our published studies indicate that physiologic low-dose CO can mitigate fibrosis in unilateral ureteral obstruction (UUO)-induced kidney fibrosis, and in bleomycin (BLM)-induced pulmonary fibrosis. Therefore, we hypothesize that RIPK3 represents an important mediator of organ fibrosis through MLKL-independent and MLKL–dependent pathways. A RIPK3-dependent (MLKL-independent) signaling pathway and downstream regulation of the FA synthesis pathway contributes to the development of kidney fibrosis. In contrast, a RIPK3 and MLKL dependent pathway can inhibit pulmonary fibrosis. Moreover, we hypothesize that CO confers protection against multi-organ fibrosis by targeting either RIPK3 and/or FA- dependent pathways. RIPK3 and/or FA-biosynthetic proteins potentially serve as diagnostic biomarkers in predicting the severity of organ fibrosis and the efficacy of CO therapy. We will test these hypotheses in the following Specific Aims: Specific Aim 1: To characterize the function of RIPK3 and MLKL in the pathogenesis of organ fibrosis; Specific Aim 2: To determine the pathogenic contribution of RIPK3-regulated fatty acid (FA) synthesis in fibrotic organs; Specific Aim 3: To determine the role of the RIPK3 and the FA synthesis pathways in the therapeutic effects of CO in experimental lung and kidney fibrosis, and in human fibrosis.

抽象的 纤维化是器官（例如肺、肾）的一种致病过程，涉及细胞外物质的过度沉积 导致器官稳态丧失的基质（ECM）是进行性慢性肾脏的标志。 疾病作为对损伤的常见致病反应同样，终末期肺部疾病也常常是这样的。 最近的研究表明，坏死性凋亡是一种基因编程的细胞形式。 由受体相互作用蛋白-1和-3（RIPK1、RIPK3）激酶调节的死亡可能正在出现 目前对于 RIPK3 在器官发病机制中的作用知之甚少。 我们有令人兴奋的初步数据表明 RIPK3 可以在实验模型中发挥关键功能。 有趣的是，缺乏 RIPK3 的小鼠，但缺乏其信号传导靶点。 我们还发现，谱系激酶结构域样蛋白（MLKL）可以预防肾纤维化。 RIPK3 介导的信号通路，通过激活 ATP 柠檬酸调节脂肪酸 (FA) 代谢 裂解酶（ACL），并导致肾纤维化，相比之下，缺乏 RIPK3 或 MLKL 的小鼠则更容易出现这种情况。 这些研究表明 RIPK3 可能是肺纤维化的一种新介质。 器官纤维化具有不同的器官或组织特异性效应。 内源性气体分子一氧化碳 (CO) 被认为是一种实验性气体分子。 我们发表的研究表明，生理性低剂量 CO 可以减轻器官损伤的治疗方式。 单侧输尿管梗阻 (UUO) 诱导的肾纤维化和博莱霉素 (BLM) 诱导的纤维化 因此，我们认为 RIPK3 是器官纤维化的重要介质。 通过 MLKL 独立和 MLKL 依赖途径。 信号通路和 FA 合成通路的下游调控有助于 相反，RIPK3 和 MLKL 依赖性途径可以抑制肺纤维化。 我们追求 CO 通过靶向 RIPK3 和/或 FA- 来预防多器官纤维化 RIPK3 和/或 FA 生物合成蛋白可能作为诊断生物标志物。 预测器官纤维化的严重程度和 CO 疗法的疗效我们将在以下实验中检验这些假设。 具体目标如下： 具体目标 1：表征 RIPK3 和 MLKL 在发病机制中的功能 器官纤维化；具体目标 2：确定 RIPK3 调节的脂肪酸 (FA) 的致病作用 纤维化器官中的合成；具体目标 3：确定 RIPK3 和 FA 合成途径的作用 CO 对实验性肺和肾纤维化以及人类纤维化的治疗作用。