A Systems Biology and Patient Stratification Approach to Improve Outcomes of Patients with Hypoxic Injury in Renal Tubular Cells in Chronic Kidney Diseases

摘要 慢性肾脏病（CKD）是一种全球性的健康流行病，并且患有CKD的患者遭受增加的肾脏损害。 死亡率和心血管疾病。尽管疾病严重，但治疗选择有限 阻碍其发展。肾小管损伤（TI）是一种常见的发现，对许多肾活检患者， CKD，并且有机制数据支持TI可导致间质纤维化和肾小管萎缩。而 间质纤维化和肾小管萎缩是已知的CKD进展的最强病理预测因子，我们 对TI如何促进这一进展的了解有限。缺氧诱导因子-1 α（HIF-1α）具有 在动物研究中显示，它会影响TI的严重程度，也已知会引发纤维化级联反应，但 关于其在肾组织中的总体活性、其细胞类型特异性活性、其相关性 与病理特征或患者结局相关。更好地理解这一途径至关重要， 几种脯氨酰羟化酶抑制剂，它们是增加HIF-1 α表达的新型治疗剂。 1α，目前正在临床试验测试中治疗CKD贫血。这项建议的第一个目的是发展一个 测量HIF-1α通路活性，可评估临床和形态学特征以及细胞类型 的特异性具体而言，候选人将a）识别与以下相关的临床和病理描述符： 增加的HIF-1α途径活性评分和B）测定HIF-1α的细胞类型特异性表达水平， 其下游组分在管状细胞中使用单细胞RNA测序。第二个目的是 该研究的目的是确定HIF-1α活性增加与预后的关系，并确定 使用生物标志物非侵入性地增加HIF-1α活性。具体而言，候选人将a）确定 增加的HIF-1α活性评分与患者结果的关联和B）鉴定血清或尿生物标志物 检测患者中HIF-1α通路活性的增加。候选人将分析3个队列的数据， 实现这些目标：肾病综合征研究网络（NEPTUNE），临床表型资源和 生物库核心（C-PROBE）和美国原住民2型糖尿病队列（以前称为Pima Indian cohort）。这些研究将使我们能够在试验中非侵入性地监测HIF-1α的活性， 患者接受新的药物，如脯氨酰羟化酶抑制剂。 候选人将获得基因表达数据分析，单细胞RNA， 排序和机器学习技术在授予期间的过程中，成功地整合 基因表达数据、病理学数据和临床数据。她将由一个专家小组指导， 在肾脏病学、肾小管损伤生物学、系统生物学和生物信息学方面具有丰富的经验。的 这些研究的长期目标是最终能够更好地分型肾小管损伤患者 基于机械术语。

ABSTRACT Chronic Kidney Disease (CKD) is a global health epidemic and patients with CKD suffer from increased mortality and cardiovascular disease. Despite the severity of the disease, there are limited treatment options to hinder its progression. Tubular injury (TI) is a common finding on many kidney biopsies from patients with CKD, and there is mechanistic data supporting that TI can lead to interstitial fibrosis and tubular atrophy. While interstitial fibrosis and tubular atrophy are the strongest known pathologic predictor of progression of CKD, we have limited understand of how TI contributes to this progression. Hypoxia Inducible Factor-1α (HIF-1α) has been shown in animal studies to impact the severity of TI and is also known to trigger a fibrotic cascade, but there is limited data regarding its overall activity in kidney tissue, its cell type specific activity, its association with pathologic features or patient outcomes. It is of utmost importance to better understand this pathway as several Prolyl Hydroxylase inhibitors, which are novel therapeutic agents that increase the expression of HIF- 1α, are currently in clinical trial testing to treat anemia of CKD. The first aim of this proposal is to develop a measure of HIF-1α pathway activity that enables evaluation of clinical and morphologic features and cell-type specificity. Specifically, the candidate will a) Identify clinical and pathologic descriptors associated with increased HIF-1α pathway activity score and b) Determine the cell-type specific expression level of HIF-1α and its downstream components in tubular cells using single-cell RNA-sequencing. The second aim of this proposal is to determine the association of increased HIF-1α activity with outcomes and identify patients with increased HIF-1α activity non-invasively using biomarkers. Specifically, the candidate will a) Determine the association of increased HIF-1α activity score with patient outcomes and b) Identify serum or urine biomarkers that detect increased HIF-1α pathway activity in patients. The candidate will analyze data from 3 cohorts to accomplish these aims: Nephrotic Syndrome Study Network (NEPTUNE), Clinical Phenotyping Resource and Biobank Core (C-PROBE) and the Native Americans with Type 2 Diabetes cohort (formerly known as the Pima Indian cohort). These investigations will allow us to monitor HIF-1α activity non-invasively in trials where patients receive novel drug agents, such as Prolyl Hydroxylase Inhibitors. The candidate will obtain formal training in analysis of gene expression data, single cell RNA- sequencing and machine learning techniques during the course of the award period to successfully integrate gene expression data, pathology data and clinical data. She will be mentored by an expert team with complementary experience in nephrology, tubular injury biology, systems biology and bioinformatics. The long-term goal of these investigations is to ultimately be able to better sub-type patients with tubular injury based on mechanistic terms.