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

SLE-AWARE：SLE——了解 APOL1 调节和表达的窗口

基本信息

批准号：
10491305
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
项目类别：
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/10491305
关键词：
Address African American population Animal Model Apolipoproteins Atherosclerosis Autoimmune Diseases Awareness Binding Biological Biological Response Modifier Therapy Biology 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 of activation protein Mentors Methods Mitochondria Modeling Necrosis Organ Outcome Pathway interactions Patients Penetrance Pharmaceutical Preparations Pharmacology Phenotype Population Positioning Attribute Primary Cell Cultures Proteins Regulation Regulatory Element Research Design Resources Respiration Rheumatology Risk Stimulus Surveys Systemic Lupus Erythematosus Testing Training Translating Variant base 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 kidney vascular structure knock-down mitochondrial dysfunction monocyte mortality novel population based promoter response risk stratification risk variant success therapeutic evaluation therapeutic target tissue injury trait transcription factor transcriptome sequencing translational scientist

项目摘要

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.

项目概要/摘要背景：大约 13% 的非裔美国人 (AA) 患有肾病和肾病心血管疾病携带两个载脂蛋白 L1 (APOL1) 基因风险变异 (RV) 拷贝。这些房车导致肾脏和心血管死亡率，但尚无治疗方法能够解决基因机制。在细胞培养和动物模型中，炎症细胞因子增加APOL1表达并使APOL1高危基因型恶化 (HRG) 相关损伤。免疫激活和由此导致的 APOL1 表达增加的程度与 APOL1 基因型协同促进狼疮性肾炎等人类疾病尚不清楚。我们将检验 APOL1 HRG SLE 患者经历恶化的疾病特征的总体假设由于 SLE 炎症介质诱导基因表达和蛋白质编码变化变异等位基因。重要的是，数量空前的生物疗法可用于药理学治疗。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，我们的团队可重复确定了 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物中，我们发现了与 SLE 相关的免疫刺激诱导 APOL1 表达。我们发现 HRG 单核细胞对高 APOL1 表达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 表达和由此产生的 HRG 相关疾病特征。方法：为了了解 APOL1 免疫调节，我们将分析 SLE 患者单核细胞转录通过 RNA-seq 分析来评估免疫通路激活。 APOL1 基因型、APOL1 转录表达、将独立且独立地测试免疫通路评分与临床结果的关联交互模型。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 数据中反映的哪些免疫系统途径与 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，并且统计遗传学、功能基因组学、免疫学、心脏病学和风湿病学。它将为未来更大规模的研究奠定基础，旨在针对 APOL1 HRG 患者的特异性免疫途径。此外，它将使 PI 成为该领域的专家。自身免疫性疾病和相关肾脏和血管合并症的功能基因组学、遗传模型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 PI 独立翻译职业的框架。