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，肾脏）的致病过程，涉及细胞外的过量沉积 矩阵（ECM）导致器官稳态丧失。纤维化是进步性慢性肾脏的标志 疾病是对损伤的常见致病反应。同样，末期肺部疾病通常是 以肺纤维化为特征。最近的研究表明，坏死性是一种遗传编程的细胞形式 由接收器相互作用蛋白-1和-3（RIPK1，RIPK3）激酶调节的死亡可能会出现 在人类疾病中的重要性。目前，RIPK3在器官发病机理中的作用鲜为人知 纤维化。我们有令人兴奋的初步数据，RIPK3可以在实验模型中执行关键功能 肾脏和肺纤维化。有趣的是，小鼠缺乏RIPK3，但没有在其信号定位的目标中混合 谱系激酶结构域样蛋白（MLKL）受到保护，以防止肾纤维化。我们还确定了 RIPK3介导的信号通路，通过激活ATP柠檬酸盐调节脂肪酸（FA）代谢 裂解酶（ACL），并有助于肾脏纤维化。相反，缺乏RIPK3或MLKL的小鼠为 容易受到肺纤维化的影响。这些研究表明RIPK3可能代表 具有差分器官或组织特异性作用的器官纤维化。 内源气态分子一氧化碳（CO）已暗示为实验 器官损伤的治疗方式。我们发表的研究表明，生理低剂量CO可以减轻 单侧输尿管反对（UUO）诱导的肾纤维化和博来霉素（BLM）诱导的纤维化 肺纤维化。因此，我们假设RIPK3代表器官纤维化的重要介体 通过独立于MLKL和MLKL依赖性途径。 RIPK3依赖性（独立MLKL） FA合成途径的信号传导途径和下游调节有助于发展 肾纤维化。相反，RIPK3和MLKL依赖性途径可以抑制肺纤维化。而且， 我们假设CO通过靶向RIPK3和/或FA-来赋予对多器官纤维化的保护 依赖途径。 RIPK3和/或FA生物合成蛋白有可能用作诊断生物标志物 预测器官纤维化的严重程度和CO治疗的效率。我们将在 以下特定目的：特定目标1：表征发病机理中RIPK3和MLKL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 纤维化器官的合成；特定目的3：确定RIPK3和FA合成途径的作用 CO在实验性肺和肾纤维化以及人类纤维化中的治疗作用中。