Targeting NLRP3 inflammasome for treating muscle complications of chronic kidney disease

工作范围（Scope of Work） 慢性肾脏病（CKD）儿童的恶病质/消瘦综合征包括厌食、身体和肌肉质量减少、营养不良和身材矮小，并且与死亡风险增加明显相关。我们的初步数据表明，阻断白细胞介素（IL）-β是最成功的逆转恶病质，指向NLRP 3炎性体的致病作用。本研究的总体目标是通过进一步了解NLRP 3信号在其病理生理学中的作用，开发CKD肌肉萎缩并发症的新疗法。假设：NLRP 3炎性体信号传导是通过特异性和靶向途径导致恶病质和肌肉萎缩的CKD共病的关键驱动因素。我们采用两种已建立的CKD小鼠模型，5/6肾切除术和胱氨酸蛋白酶基因敲除（Ctns[-/-]-）小鼠。为了验证这一假设，我们提出了以下目标：阐明NLRP 3炎性体信号通路在病理生理学中的作用，并作为CKD恶病质新疗法的靶点。我们将研究CKD相关恶病质患者外周血单核细胞（PBMC）、脂肪和肌肉中NLRP 3信号的时间序列。我们将把这项研究扩展到CKD儿童，看看PBMC中的NLRP 3信号是否是脂肪和肌肉表达的替代品。我们将使用髓系特异性NLRP 3敲除模型来研究循环髓系细胞的作用。最后，我们将研究使用CRID 3（MCC 950）药物阻断NLRP 3和使用阿那白滞素（anakinra）药物阻断IL-1 β对CKD恶病质的影响。我们目标的完成将满足未满足的临床需求，从而改善长期结局。

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.