Modulation of Macrophage Function through Alternative Splicing in Cardiometabolic Diseases

通过选择性剪接调节心脏代谢疾病中的巨噬细胞功能

基本信息

批准号：
9547928
负责人：
Jennie J LIn
金额：
$ 16.28万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9547928
关键词：
Address Affect Alleles Alternative Splicing Animal Model Apolipoprotein E Apoptosis Area Atherosclerosis Attenuated Biology Cell Proliferation Cell Survival Cells Chronic Code Collaborations Complex Coronary Arteriosclerosis Development Development Plans Disease Environment Event Exclusion Exons Foam Cells Fostering Functional disorder Funding Future Generations Genes Genetic Genomics Homeostasis Human Human Genome Inflammation Inflammatory Interferon Type II Interleukin-4 Investigation Lead Light Link Lipids Low-Density Lipoproteins Macrophage Activation Mentors Messenger RNA Metabolic Pathway Minor Morbidity - disease rate Mus Pathogenesis Pathway interactions Pennsylvania Phenotype Physicians Play Post-Transcriptional Regulation Principal Investigator Protein Isoforms Proteins RNA Splicing Research Research Training Rest Role Scientist Stimulus Stress Structural Protein Structure Therapeutic Tissues Training Transcript Universities Variant atherogenesis base cardiometabolism career career development effective therapy functional genomics gene function genetic variant genome editing human disease human model in vivo induced pluripotent stem cell insight knock-down lipid metabolism macrophage medical schools monocyte mortality multidisciplinary novel precision medicine protein structure response therapeutic target training opportunity transcriptome sequencing translational scientist

项目摘要

PROJECT SUMMARY This application is for Dr. Jennie Lin to develop her career as an academic physician-scientist focusing on the functional genomics of cardiometabolic diseases. The career development plan includes training in mRNA processing, macrophage biology, genome editing, and animal models of human disease, with formal mentoring by Dr. Kiran Musunuru and Dr. Daniel Rader along with a multi-disciplinary committee of distinguished scientists. The proposed studies and structured mentored activities will take place at the Perelman School of Medicine at the University of Pennsylvania, which offers a remarkably rich research and training environment that will foster Dr. Lin's professional development. The proposed research will focus on how key alternative splicing (AS) events contribute to the pathophysiology of cardiometabolic diseases, which continue to incur significant morbidity and mortality worldwide. Associated with chronic systemic inflammation, cardiometabolic diseases such as atherosclerosis involve the activation of macrophages to shift toward a causally implicated pro-inflammatory phenotype, but the mechanisms underlying this shift remain incompletely understood. Although transcript-level changes have previously been characterized, a missing link in our understanding of macrophage plasticity and function is whether post-transcriptional regulation is involved.! With the advent of RNA sequencing (RNA-seq), AS − the generation of multiple different mRNA isoforms from a single gene − is emerging as a pervasive cell-specific mechanism that can lead to human diseases if dysregulated. Because AS plays an impactful role in cellular differentiation, it may contribute to the phenotypic plasticity of activated macrophages and hence the pathogenesis of cardiometabolic diseases. Although few studies describe isoform-level differences in the extremes of macrophage phenotypes, our preliminary RNA-seq studies of activated and resting human monocyte-derived macrophages have identified more than 200 AS events for genes associated with inflammation and cell survival. This proposal outlines a plan to study how AS events in macrophages for two specific genes contribute to inflammatory and metabolic pathways relevant to cardiometabolic diseases and, in particular, atherosclerosis. The first gene is PLD1, which has known roles in lipid processing and undergoes increased inclusion of exon 16 in pro-inflammatory macrophages. The second gene is ZC3HC1, which houses in its alternative exon 8 a genetic variant associated with coronary artery disease. The proposed studies include two parallel aims that will investigate for each of these genes how AS alters (1) macrophage inflammatory phenotype, (2) metabolic pathways relevant to gene function and atherogenesis, and (3) the development and progression of atherosclerosis in vivo. In undertaking the proposed studies and training plan, the Dr. Lin will elucidate novel mechanisms of macrophage function in the cardiometabolic context, mature as an independent translational investigator in functional genomics, and prepare to compete successfully for R01 funding for future projects aimed at precision medicine.

项目摘要该申请是詹妮·林博士（Jennie Lin 心脏代谢疾病的功能基因组学。职业发展计划包括mRNA的培训加工，巨噬细胞生物学，基因组编辑和人类疾病的动物模型，并具有正式的心理 Kiran Musunuru博士和Daniel Rader博士以及杰出的多学科委员会科学家。拟议的研究和结构化重要的活动将在Perelman学校举行宾夕法尼亚大学的医学，提供了非常丰富的研究和培训环境这将促进林博士的专业发展。拟议的研究将重点介绍如何关键选择剪接（AS）事件有助于心脏代谢性疾病的病理生理学，继续产生全世界的大量发病率和死亡率。与慢性全身性炎症，心脏代谢相关诸如动脉粥样硬化之类的疾病涉及巨噬细胞的激活朝着随便的涉及促炎的表型，但是这种转变的基础机制仍未完全理解。尽管先前已经表征了笔录级的变化，但我们对巨噬细胞的塑性和功能是是否涉及转录后调节。随着冒险的冒险 RNA测序（RNA-Seq），AS- - 从单个基因 - IS的多个不同mRNA同工型的产生出现是一种普遍的细胞特异性机制，如果失调，可能导致人类疾病。因为由于在细胞分化中起有影响力的作用，它可能有助于激活的表型可塑性巨噬细胞以及心脏代谢疾病的发病机理。尽管很少有研究描述同工型级巨噬细胞表型的极端差异，我们的初步RNA-seq研究激活和静止的人类单核细胞衍生的巨噬细胞已确定200多个事件与感染和细胞存活相关的基因。该提案概述了研究如何作为事件的计划两个特定基因的巨噬细胞有助于与心脏代谢疾病，尤其是动脉粥样硬化。第一个基因是PLD1，它在脂质加工和经历增加了外显子16在促炎性巨噬细胞中的包含。第二个基因是ZC3HC1，它在其替代外显子8中容纳与冠状动脉相关的遗传变异疾病。拟议的研究包括两个平行目的，这些目标将研究每个基因中的每个基因变化（1）巨噬细胞炎症表型，（2）与基因功能相关的代谢途径动脉粥样硬化，以及（3）体内动脉粥样硬化的发展和进展。在进行拟议的研究和培训计划，林博士将阐明巨噬细胞功能的新机制心脏代谢环境，作为功能基因组学独立翻译研究者成熟，并且准备成功竞争R01资金，以提供针对精密医学的未来项目。