SLE-AWARE: SLE-- A Window into APOL1 Regulation andExpression

SLE-AWARE：SLE——了解 APOL1 调节和表达的窗口

• 批准号: 10686323
• 负责人: Ashira Deshon Blazer
• 金额: $ 19.76万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686323
• 关键词: Address; African American population; Animal Model; Apolipoproteins; Atherosclerosis; Autoimmune Diseases; Awareness; Binding; Biological Response Modifier Therapy; Biological Response Modifiers; Biology; Blood Vessels; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cell Death; Chronic; Clinical; Code; Complex; Computational Technique; Data; Defect; Disease; Disease Outcome; End stage renal failure; Endothelial Cells; Exhibits; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genotype; Goals; HIV; Human; Hypersensitivity; Hypertension; Immune; Immune system; Immunologics; Immunology; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Injury to Kidney; Interferons; Kidney; Kidney Diseases; Laboratories; Lupus Nephritis; Mediating; Mediator; Mentors; Methods; Mitochondria; Modeling; Necrosis; Organ; Outcome; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Primary Cell Cultures; Proteins; Regulation; Regulatory Element; Reproducibility; Research Design; Resources; Respiration; Rheumatology; Risk; Stimulus; Surveys; Systemic Lupus Erythematosus; Testing; Training; Translating; Variant; candidate identification; career; career development; chronic inflammatory disease; cohort; collaborative environment; comorbidity; cytokine; cytotoxicity; disease phenotype; experience; functional genomics; gene environment interaction; genetic variant; genotyped patients; high risk; human disease; immune activation; immunoregulation; innovation; kidney dysfunction; knock-down; mitochondrial dysfunction; monocyte; mortality; novel; pharmacologic; population based; promoter; response; risk stratification; risk variant; success; synergism; therapeutic evaluation; therapeutic target; tissue injury; trait; transcription factor; transcriptome sequencing; translational scientist

PROJECT SUMMARY/ABSTRACT Background: Approximately 13% of African Americans (AA), who suffer disproportionately from kidney and cardiovascular disease, carry two copies of the Apolipoprotein L1 (APOL1) gene risk variants (RV). These RVs contribute to renal and cardiovascular mortality, yet no therapies address gene mechanism. In cell culture and animal models, inflammatory cytokines increase APOL1 expression and worsen APOL1 high-risk genotype (HRG) related injury. The degree to which immune activation and resultant increased APOL1 expression synergizes with APOL1 genotype to precipitate human disease, such as lupus nephritis, is not understood. We will test the overarching hypothesis that APOL1 HRG SLE patients experience worsened disease features both due to SLE inflammatory mediators which induce gene expression and to protein coding changes carried on the variant allele. Importantly, an unprecedented number of biologic therapies are available to pharmacologically modulate immune pathways. Therefore understanding the relative contribution of specific immune pathways to APOL1 HRG associated disease may offer new treatment opportunities in this sensitive population. Preliminary Data: In our unique, AA SLE cohort and Ghanaian replication cohort, our group reproducibly identified APOL1 HRG associated traits including hypertension, renal dysfunction, and early atherosclerosis. Both in SLE monocytes and primary monocyte cell cultures, we identified SLE-relevant immune stimuli that induce APOL1 expression. We showed that HRG monocytes in response to high APOL1 expression exhibit mitochondrial dysfunction. These findings have clinical implications as they support a strategy aimed at reducing immune activation to mitigate APOL1 expression and resultant HRG associated disease features. Methods: To understand APOL1 immune regulation, we will analyze SLE patient monocyte transcriptional profiles by RNA-seq to assess immune pathway activation. APOL1 genotype, APOL1 transcriptional expression, and immune pathway scores will be tested for association with clinical outcomes, independently and in interaction models. We will determine whether increased APOL1 expression synergizes with risk genotype, and which immune system pathways reflected in the RNA-seq data are associated with APOL1 expression. We will validate the human transcriptional analysis using in-vitro monocyte cell culture models. Objectives and Career Development: This proposal leverages unique clinical and laboratory resources, and highly collaborative environment between experts in statistical genetics, functional genomics, immunology, cardiology, and rheumatology. It will lay the groundwork to propose future larger-scale studies designed to target specific immune pathways in APOL1 HRG patients. Furthermore, it will allow the PI to become an expert in the functional genomics of autoimmune disease and related kidney and vascular comorbidities, genetic modeling in complex clinical traits, and innovative laboratory and computational techniques. Thus, this will provide a framework for the PI’s independent translational career.

项目摘要/摘要 背景：大约13%的非裔美国人(AA)，他们患有不成比例的肾脏和 心血管疾病，携带两份载脂蛋白L1(APOL1)基因风险变体(RV)。这些房车 导致肾脏和心血管疾病死亡，但目前还没有针对基因机制的治疗方法。在细胞培养和 动物模型，炎性细胞因子增加APOL1表达并恶化APOL1高危基因 (HRG)相关伤害。免疫激活和由此导致的APOL1表达增加的程度 与APOL1基因协同作用可导致人类疾病，如狼疮性肾炎，目前尚不清楚。我们 将检验APOL1 HRG SLE患者经历疾病特征恶化的首要假设 由于系统性红斑狼疮炎症介质诱导基因表达和蛋白质编码的改变进行 变异等位基因。重要的是，有空前数量的生物疗法可用于药物治疗。 调节免疫途径。因此，了解特定免疫途径对 APOL1 HRG相关疾病可能为这一敏感人群提供新的治疗机会。 初步数据：在我们独特的AA SLE队列和加纳复制队列中，我们的组可重复 已确定的APOL1 HRG相关特征包括高血压、肾功能障碍和早期动脉粥样硬化。 在SLE单核细胞和原代单核细胞培养中，我们确定了与SLE相关的免疫刺激 诱导APOL1的表达。我们发现HRG单核细胞对高表达APOL1的反应表现出 线粒体功能障碍。这些发现具有临床意义，因为它们支持旨在减少 免疫激活，以减轻APOL1的表达和由此产生的HRG相关疾病特征。 方法：通过分析SLE患者单核细胞转录水平，了解APOL1的免疫调节作用 用rna-seq分析以评估免疫途径的激活。APOL1基因，APOL1转录表达， 免疫途径评分将被测试与临床结果的相关性，独立和 交互模型。我们将确定APOL1表达增加是否与风险基因型协同作用，以及 RNA-SEQ数据中反映的免疫系统途径与APOL1的表达有关。 我们将使用体外单核细胞培养模型来验证人类转录分析。 目标和职业发展：该计划利用独特的临床和实验室资源，以及 统计遗传学、功能基因组学、免疫学专家之间的高度协作环境， 心脏病和风湿病。它将为提出未来更大规模的研究奠定基础，旨在 APOL1-HRG患者的特异性免疫途径此外，它将使私家侦探成为 自身免疫性疾病及相关肾脏和血管合并症的功能基因组学 复杂的临床特征，以及创新的实验室和计算技术。因此，这将提供一个 国际翻译协会独立翻译事业的框架。