C-reactive protein mediated signals in renal injury and repair

C反应蛋白介导的肾损伤和修复信号

• 批准号: 9259103
• 负责人: Rachel V Jimenez
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259103
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Acute-Phase Proteins; Affect; Animals; Area; Attenuated; Bilateral; Binding Proteins; Biological Markers; Bone Marrow; C-reactive protein; Cell Line; Cessation of life; Chronic Kidney Failure; Communication; Data; Development; Disease; Doctor of Philosophy; Doctor' s Degree; Dose; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Event; Fc Receptor; Fc gamma receptor IIB; Fibrosis; Filtration; Functional disorder; Glycogen Synthase Kinase 3; Goals; Harvest; Healthcare; Human; Immunologist; Immunology; Impairment; In Vitro; Inflammation; Inflammatory Response; Injury; Kidney; Knockout Mice; Knowledge; Laboratories; Lead; Link; Literature; Mediating; Mentorship; Modeling; Molecular; Monitor; Mouse Protein; Mus; Myelogenous; Nephrology; Nutrient; Operative Surgical Procedures; Outcome; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Positioning Attribute; Prevention; Principal Investigator; Problem Solving; Process; Protein Dephosphorylation; Protein Isoforms; Protein Kinase; Publishing; Recovery; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; Research Proposals; Research Training; Resolution; Role; Scientist; Serine; Signal Pathway; Signal Transduction; Suppressor-Effector T-Lymphocytes; Survivors; Techniques; Testing; Time; Tissues; Training; Transgenic Mice; Transgenic Organisms; Tubular formation; Wild Type Mouse; base; cell injury; economic cost; effective therapy; experimental study; glycogen synthase kinase 3 beta; improved; in vivo; injured; injury and repair; kidney cell; mouse model; new therapeutic target; novel; novel therapeutics; pre-doctoral; prevent; renal ischemia; repaired; response; skill acquisition; skills; social; success; training opportunity

Abstract Acute kidney injury (AKI) is a major healthcare concern, affecting ~13.3 million patients per year world-wide and causing ~1.7 million deaths. Despite the resolution of renal injury in many survivors, patients with AKI are predisposed to developing chronic kidney disease. Easing this burden will require new and effective therapies, but their development has been hindered by the limited knowledge of the injury mechanisms in AKI. A common cause of AKI is renal ischemia/reperfusion injury (IRI), characterized by impairment of oxygen and nutrient supply triggering renal tubular epithelial cell (TEC) injury upon reperfusion. Renal IRI is accompanied by a systemic inflammatory response, but the contribution of this response to AKI is not fully understood. Our group showed that a recognized biomarker of inflammation, C-reactive protein (CRP), exacerbates injury in a human CRP transgenic (CRPtg) mouse model of bilateral renal IRI. The worsened outcome seen in CRPtg mice involves human CRP-mediated alteration of the subtypes of myeloid derived suppressor cells (MDSCs) infiltrating the injured kidney. Indeed, targeted lowering of human CRP prior to renal IRI both normalizes MDSC subtype balance and protects the kidney. Relevant literature show that both pharmacological inhibition of glycogen synthase kinase 3 (GSK3) and specific renal proximal TEC deletion of the beta isoform (GSK3β) attenuate AKI and later renal fibrosis, suggesting a role for GSK3 kinase activity in balancing successful and maladaptive renal repair after AKI. My preliminary data shows that CRP dose-dependently modulates GSK3β phosphorylation (and thus GSK3β kinase activity) in vitro in wild type bone marrow-derived MDSCs. I therefore hypothesize that CRP binding to the inhibitory type Fc gamma receptor IIB (FcγRIIB), which is expressed by renal cells such as MDSCs and TECs, leads to downstream modulation of GSK3β kinase activity, thereby effecting signaling cascades propelling AKI. Through studying this novel causal signaling pathway new therapeutic targets for AKI could be revealed. In addition, this project describes the dissertation research that corresponds to the pre-doctoral training planned in cooperation between the Principal Investigator (myself), Sponsor (Alexander Szalai, PhD), and Co-Sponsor (Anupam Agarwal, MD). This project will provide me an opportunity for skill development in molecular, cellular, and immunohistochemical techniques, mouse disease and surgical manipulation, analysis of the mechanisms and processes underlying a pathophysiological response and therein the human translatable applications. The successful completion of the research and training detailed within this project would therefore produce a highly proficient Immunologist specialized in Nephrology with a range of skills applicable to many research areas.

摘要 急性肾损伤（阿基）是一个主要的医疗保健问题，每年影响全球约1330万患者 造成约170万人死亡。尽管许多幸存者的肾损伤得到了解决，但阿基患者仍 易患慢性肾病减轻这一负担将需要新的和有效的疗法， 但由于对阿基损伤机制的认识有限，阻碍了其发展。一个共同 阿基的原因是肾缺血/再灌注损伤（IRI），其特征在于氧和营养的损害 再灌注时，供应触发肾小管上皮细胞（TEC）损伤。肾IRI伴有 全身性炎症反应，但这种反应对阿基的贡献还不完全清楚。我们集团 表明，一种公认的炎症生物标志物C反应蛋白（CRP）会加剧人类的损伤， 双侧肾IRI的CRP转基因（CRPtg）小鼠模型。在CRPtg小鼠中观察到的恶化结局 涉及人CRP介导的髓源性抑制细胞（MDSC）亚型的改变 渗入受损的肾脏事实上，在肾IRI之前靶向降低人CRP可以使MDSC正常化 平衡亚型，保护肾脏。相关文献表明，药理学抑制 糖原合成酶激酶3（GSK 3）和β亚型（GSK 3 β）的特异性肾近端TEC缺失 减轻阿基和随后的肾纤维化，表明GSK 3激酶活性在平衡成功和 阿基后的适应不良肾修复。我的初步数据显示，CRP剂量依赖性地调节GSK 3 β 因此，在野生型骨髓来源的MDSC中，在体外可以观察到GSK 3 β磷酸化（以及因此的GSK 3 β激酶活性）。因此我 假设CRP与抑制型Fc γ受体IIB（FcγRIIB）结合， 肾细胞，如MDSC和TEC，导致GSK 3 β激酶活性的下游调节， 影响推动阿基的信号级联。通过研究这一新的因果信号通路， 阿基的治疗靶点。此外，本项目还介绍了本论文的研究工作， 对应于主要研究者（本人）合作计划的博士前培训， 申办者（亚历山大Szalai，PhD）和共同申办者（Anupam Agarwal，MD）。这个项目将为我提供一个 在分子，细胞和免疫组织化学技术，小鼠疾病的技能发展的机会 和手术操作，分析病理生理学的机制和过程， 这是人类的回应，也是人类可翻译的应用。研究的顺利完成， 因此，本项目中的详细培训将培养出一名高度熟练的免疫学家， 肾脏病学与适用于许多研究领域的一系列技能。