Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome

摘要 心力衰竭影响着650万美国人，每年新增病例近100万例，每年造成超过300亿美元的损失 医疗保健资源。肾功能不全(RD)在HF中很常见，据报道患病率超过50%， 死亡的主要风险因素。最终，心功能不全促进肾脏纤维化重塑和 进行性心衰引起的RD，一种被称为心肾综合征(CRS)的病理生理状况。重要的是 心力衰竭的RD是生存率下降的一个强有力的标志，表现优于传统的心力衰竭严重程度指标，如 射血分数和功能等级，但对这一过程背后的机制进行了基础研究 是有限的。纤维化之前的一些因素有助于CRS的发展，包括 血流动力学、神经激素、细胞因子和交感神经系统(SNS)激活。响应 这些变化都是白细胞，包括中性粒细胞、单核细胞、巨噬细胞和淋巴细胞， 其中一些与CRS有牵连。然而，很少有报道调查他们是否扮演了 反应性或致死性在CRS所致肾功能障碍和反应性重塑中的作用 或如何减轻其在这一过程中的影响。我们假设白细胞在 调节CRS，由于RD仍然是心力衰竭患者预后不良的强大独立预测因子， 了解白细胞的作用及其在CRS进展过程中所经历的分子变化可能 提供降低患者死亡率的新策略。因此，我们将确定时间和 心、肾结构和功能改变与亚型特异性白细胞浸润的关系 在CRS进程中，在特定时间点删除它们的影响，以及执行动态单次 慢性肾综合征患者肾细胞转录组分析及外周血转录组分析 临床表现为CRS的小鼠和人类的白细胞。此外，我们的实验室最近显示， 白细胞特异性β2肾上腺素能受体(β2AR)表达或信号的调节改变白细胞 GRK/β-arrestin(βARR)依赖的靶向性和对损伤的反应。因此，我们 将确定白细胞特异性β2AR依赖信号对CRS进展的影响，并确定如何 基因缺失、药物抑制或GRK/βARR偏向调节白细胞β2AR信号的影响 CRS的发展和进展。该项目的完成将产生新的分子和生理 通过靶向白细胞依赖性过程检测和治疗心力衰竭所致CRS的研究进展 和响应性。

Summary HF affects 6.5 million Americans, with almost 1 million new cases per year and costing over $30 billion in healthcare resources. Renal dysfunction (RD) is common in HF, with a reported prevalence over 50%, and is a major risk factor for death. Ultimately, cardiac dysfunction promotes renal fibrotic remodeling and progressive HF-induced RD, a pathophysiologic condition known as cardiorenal syndrome (CRS). Importantly, RD in HF is a potent marker of decreased survival, outperforming traditional metrics of HF disease severity like ejection fraction and functional class, however fundamental research into the mechanisms behind this process are limited. A number of factors preceding fibrosis contribute to the development of CRS, including changes in hemodynamics, neurohormones, cytokines and sympathetic nervous system (SNS) activation. Responsive to each of these changes are leukocytes, including neutrophils, monocytes, macrophages and lymphocytes, some of which have been implicated in CRS. However, few reports have investigated whether they play a reactionary or causative role in the development of CRS-induced renal dysfunction and remodeling in response to HF or how to mitigate their impact in this process. We hypothesize that leukocytes play a fundamental role in regulating CRS, and since RD remains a strong independent predictor for poor prognosis in HF patients, understanding the role of leukocytes and the molecular changes they undergo during CRS progression may offer new strategies by which to alleviate patient mortality. Therefore, we will determine the temporal- and subtype-specific leukocyte infiltration profiles in relation to changes in cardiac and renal structure and function during CRS progression, the impact of their deletion at specific timepoints, as well as perform a dynamic single cell transcriptome analysis of renal cells during CRS and transcriptome analyses of peripheral blood leukocytes from mice and humans with clinically-manifested CRS. In addition, our lab recently showed that modulation of leukocyte-specific β2-adrenergic receptor (β2AR) expression or signaling alters leukocyte targeting and responsiveness to injury in a GPCR kinase (GRK)/β-arrestin (βarr)-dependent manner. Thus, we will define the impact of leukocyte-specific β2AR-dependent signaling on CRS progression and determine how genetic deletion, pharmacologic inhibition or GRK/βarr-biased modulation of leukocyte β2AR signaling impacts CRS development and progression. Completion of this project will generate new molecular and physiologic insight toward the detection and treatment of HF-induced CRS via targeting of leukocyte-dependent processes and responsiveness.