Targeting NLRP3 inflammasome for treating muscle complications of chronic kidney disease

靶向 NLRP3 炎性体治疗慢性肾病的肌肉并发症

• 批准号: 10240309
• 负责人: ROBERT H MAK
• 金额: $ 23.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240309
• 关键词: 10 year old; Anorexia; Bone Density; Bone Diseases; Bone Growth; CASP1 gene; Cachexia; Child; Chronic Disease; Chronic Kidney Failure; Clinical; Complication; Crystallization; Cysteamine; Cystine; Cystinosis; Data; Dietary Calcium; Dietary Phosphorus; Disease; Disease Outcome; Dual-Energy X-Ray Absorptiometry; End stage renal failure; Exhibits; FDA approved; Failure; Fanconi Syndrome; Fatty acid glycerol esters; Fracture; Functional disorder; Genes; Goals; Growth; High Prevalence; Immune signaling; Immunohistochemistry; Incidence; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukins; Investigation; Kidney; Knock-out; Length; MRI Scans; Measurement; Measures; Modeling; Multiprotein Complexes; Mus; Muscle; Muscle function; Muscular Atrophy; Mutation; Myelogenous; Myeloid Cells; Nephrectomy; Obesity; Outcome; PTH gene; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phenotype; Prevention; Production; Publishing; Quality of life; Receptor Signaling; Recombinants; Regulation; Research; Role; Scanning; Signal Pathway; Signal Transduction; Surrogate Markers; Testing; Tissues; Wasting Syndrome; Weight; Work; anakinra; bone; bone strength; bone turnover; cancer cachexia; comorbidity; fracture risk; improved; in vivo; infancy; inhibitor/antagonist; mortality; mortality risk; mouse model; muscle form; nephropathic cystinosis; new therapeutic target; novel strategies; novel therapeutics; nutrition; receptor; response; transcriptome sequencing; translational impact; translational study; wasting

SUMMARY(Scope of Work) The cachexia/wasting syndrome in children with chronic kidney disease (CKD) consists of anorexia, reduced body and muscle mass, poor nutrition and short stature, and has been clearly associated with increased mortality risk. Our preliminary data show that blocking interleukin (IL)-Beta is most successful at reversing cachexia, pointing toward a pathogenic role for the NLRP3 inflammasome. The overarching goal of this research is to develop novel therapy of the muscle wasting complication of CKD by further understanding of NLRP3 signaling in its pathophysiology. Hypothesis: NLRP3 inflammasome signaling is a key driver of CKD comorbidities of cachexia, and muscle wasting through specific and targetable pathways. We employ two established CKD mouse models, 5/6 nephrectomy and the cystinosis knockout (Ctns[-/-]-) mouse. To test this hypothesis, we propose the following aim: To elucidate the role of the NLRP3 inflammasome signaling pathway in the pathophysiology and as a target for novel therapy of CKD cachexia. We will study the temporal sequence of NLRP3 signature in peripheral blood mononuclear cells (PBMCs), fat and muscle in CKD associated cachexia. We will extend this investigation to children with CKD to see if NLRP3 signature in PBMCs is a surrogate for fat and muscle expression. We will use a myeloid specific NLRP3 knockout model to study the role of circulating myeloid cells. Finally, we will investigate the impact of pharmacologic blockade of NLRP3 using CRID3(MCC950) and of IL-1Beta using anakinra on CKD cachexia. Completion of our aim will fulfill an unmet clinical need leading to improvement in long- term outcomes.

总结(工作范围) 慢性肾脏疾病(CKD)儿童的恶病质/消瘦综合征包括食欲减退、身体和肌肉质量减少、营养不良和身材矮小，显然与死亡风险增加有关。我们的初步数据显示，阻断白细胞介素β在逆转恶病质方面最成功，这表明NLRP3炎症小体具有致病作用。这项研究的主要目标是通过进一步了解NLRP3信号在CKD的病理生理学中的作用，开发新的治疗CKD肌肉萎缩并发症的方法。假设：NLRP3炎症小体信号是CKD恶病质和肌肉萎缩共病的关键驱动因素，通过特定和靶向的途径。我们采用了两种已建立的CKD小鼠模型，5/6肾切除和胱氨酸病基因敲除(CTNS[-/-]-)小鼠。为了验证这一假说，我们提出了以下目标：阐明NLRP3炎症体信号通路在CKD恶病质的病理生理中的作用，并作为新的治疗靶点。我们将研究CKD相关恶病质患者外周血单个核细胞(PBMC)、脂肪和肌肉中NLRP3信号的时间序列。我们将把这项研究扩展到CKD儿童，看看PBMCs中的NLRP3签名是否可以替代脂肪和肌肉的表达。我们将使用髓系特异性的NLRP3基因敲除模型来研究循环中髓系细胞的作用。最后，我们将研究使用CRID3(MCC950)的药物阻断NLRP3和使用Anakinra的IL-1β对CKD恶病质的影响。完成我们的目标将满足未得到满足的临床需求，从而改善长期结果。