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％的非洲裔美国人（AA），他们因肾脏和 心血管疾病，携带两份载脂蛋白L1（APOL1）基因风险变体（RV）的副本。这些RV 有助于肾脏和心血管死亡率，但没有疗法解决基因机制。在细胞培养和 动物模型，炎性细胞因子会增加APOL1的表达，而APOL1高风险基因型较差 （HRG）相关伤害。免疫激活和结果增加Apol1表达的程度 与APOL1基因型协同作用，以沉淀人类疾病，例如狼疮肾炎，尚不清楚。我们 将检验总体假设，即Apol1 HRG SLE患者经历了被遗忘的疾病特征 由于SLE炎症介质引起基因表达和蛋白质编码的变化在 变体等位基因。重要的是，可以在药品上使用前所未有的生物疗法 调节免疫途径。因此了解特定免疫途径对 APOL1 HRG相关疾病可能会在这种敏感人群中提供新的治疗机会。 初步数据：在我们独特的AA SLE队列和加纳复制队列中，我们的小组可重现 确定了APOL1 HRG相关的性状，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物中，我们都确定了与SLE相关的免疫抑制剂 诱导apol1表达。我们表明，HRG单核细胞响应高apol1表达展览 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的策略 免疫激活以减轻APOL1表达和由HRG相关的疾病特征。 方法：了解APOL1免疫调节，我们将分析SLE患者单核细胞的转录 RNA-Seq的曲线以评估免疫途径激活。 apol1基因型，apol1转录表达， 并将对免疫道路分数进行测试，以与临床结果相关，独立和中 交互模型。我们将确定增加的Apol1表达是否与风险基因型协同作用，并且 RNA-seq数据中反映的免疫系统途径与APOL1表达相关。 我们将使用体外单核细胞培养模型验证人类转录分析。 目标和职业发展：该提案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，免疫学专家之间的高度协作环境， 心脏病学和风湿病。它将为未来的大规模研究提出基础，旨在针对 APOL1 HRG患者的特定免疫途径。此外，它将允许PI成为专家 自身免疫性疾病以及相关肾脏和血管合并症的功能基因组学，遗传建模 复杂的临床特征以及创新的实验室和计算技术。那将提供一个 PI独立翻译生涯的框架。