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: 10629911
• 负责人: Ashira Deshon Blazer
• 金额: $ 13.72万
• 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/10629911
• 关键词: SLE; AWARE; Window; into; APOL1

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.

项目总结/摘要 背景：大约13%的非洲裔美国人（AA），他们不成比例地患有肾脏疾病， 心血管疾病，携带载脂蛋白L1（APOL 1）基因风险变体（RV）的两个副本。这些RV 导致肾脏和心血管死亡，但没有治疗方法解决基因机制。在细胞培养和 在动物模型中，炎性细胞因子增加APOL 1表达并恶化APOL 1高危基因型 (HRG)相关伤害。免疫激活和结果增加APOL 1表达的程度 与APOL 1基因型协同作用以促进人类疾病，如狼疮性肾炎，尚不清楚。我们 将检验APOL 1 HRG SLE患者的疾病特征恶化的总体假设， 由于诱导基因表达的SLE炎症介质和在细胞表面进行的蛋白质编码改变， 变异等位基因重要的是，有数量空前的生物疗法可用于治疗癌症。 调节免疫途径。因此，了解特异性免疫途径的相对贡献， APOL 1 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，我们的组可重复地 鉴定了APOL 1 HRG相关性状，包括高血压、肾功能不全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，我们鉴定了SLE相关的免疫刺激物， 诱导APOL 1表达。我们发现HRG单核细胞对APOL 1高表达的反应表现为： 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APOL 1表达和由此产生的HRG相关疾病特征。 方法：通过分析SLE患者单核细胞的转录水平，了解APOL 1的免疫调节， 通过RNA-seq分析来评估免疫途径活化。APOL 1基因型，APOL 1转录表达， 和免疫途径评分将被测试与临床结果的相关性，独立地， 互动模式我们将确定APOL 1表达增加是否与风险基因型协同作用， RNA-seq数据中反映的免疫系统途径与APOL 1表达相关。 我们将使用体外单核细胞培养模型验证人转录分析。 目标和职业发展：该提案利用独特的临床和实验室资源， 统计遗传学、功能基因组学、免疫学 心脏病学和风湿病学。它将为提出未来更大规模的研究奠定基础， APOL 1 HRG患者的特异性免疫途径。此外，它将使PI成为 自身免疫性疾病及相关肾脏和血管共病的功能基因组学， 复杂的临床特征，以及创新的实验室和计算技术。这将提供一个 为PI的独立翻译职业生涯提供框架。