Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome

总结 HF影响650万美国人，每年有近100万新病例，每年花费超过300亿美元。 医疗资源。肾功能不全（RD）在HF中很常见，据报道患病率超过50%， 一个主要的死亡风险因素最终，心脏功能障碍促进肾纤维化重构， 进行性HF诱导的RD，一种称为心肾综合征（CRS）的病理生理学状况。重要的是， HF中的RD是存活率降低的有效标志物，优于HF疾病严重程度的传统指标， 射血分数和功能分类，然而，对这一过程背后的机制的基础研究 是有限的。纤维化之前的许多因素有助于CRS的发展，包括纤维化的变化。 血液动力学、神经激素、细胞因子和交感神经系统（SNS）激活。响应于 这些变化中的每一种都是白细胞，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有关。然而，很少有报告调查他们是否发挥了作用。 在CRS诱导的肾功能不全的发展中起反应性或致病性作用， 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，并且由于RD仍然是HF患者预后不良的强独立预测因子， 了解白细胞的作用及其在CRS进展过程中的分子变化， 提供新的策略来降低病人的死亡率。因此，我们将确定时间-和 与心脏和肾脏结构和功能变化相关的亚型特异性白细胞浸润特征 在CRS进展期间，在特定时间点删除它们的影响，以及进行动态单次 CRS期间肾细胞的细胞转录组分析和外周血的转录组分析 来自具有临床表现的CRS的小鼠和人的白细胞。此外，我们的实验室最近表明， 调节白细胞特异性β2-肾上腺素能受体（β2AR）表达或信号转导改变白细胞 以GPCR激酶（GRK）/β-抑制蛋白（β-arrestin，β-AR）依赖性方式靶向和响应损伤。因此我们 将定义白细胞特异性β 2AR依赖性信号传导对CRS进展的影响，并确定如何 白细胞β2AR信号转导的遗传缺失、药物抑制或GRK/β arr偏向性调节影响 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HF诱导的CRS 和响应能力。

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.