Identifying novel networks of candidate Atrial Fibrillation genes in the Drosophila cardiac aging model

识别果蝇心脏衰老模型中候选心房颤动基因的新网络

• 批准号: 10155141
• 负责人: James Kezos
• 金额: $ 6.86万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155141
• 关键词: Action Potentials; Address; Affect; Age; Aging; Arrhythmia; Atrial Fibrillation; Biological Models; CRISPR/Cas technology; Calcium; Calcium Signaling; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Complex; Data; Diet; Disease; Drosophila genus; Drug Targeting; Ectopic Expression; Educational process of instructing; Environment; Environmental Risk Factor; Enzymes; Epidemic; Equipment; Etiology; Exhibits; Fatty acid glycerol esters; Fibrinogen; Fibrosis; General Population; Generations; Genes; Genetic; Genetic Predisposition to Disease; Heart; Heart Atrium; Heart Diseases; Heart failure; High Fat Diet; Homeostasis; Human; Incidence; Individual; Investigational Therapies; Laboratories; Link; Lipids; Long QT Syndrome; Longevity; Measures; Mediating; Metabolic; Modeling; Molecular; Myocardial dysfunction; Network-based; Obesity; Organ; Pathogenesis; Pathway interactions; Phenotype; Phospholipids; Population; Positioning Attribute; Postdoctoral Fellow; Potassium Channel; Predisposition; Production; Pump; Quality of life; Regulator Genes; Research; Research Personnel; Research Training; Resource Sharing; Risk Factors; Role; Scientist; Small Interfering RNA; Stearoyl-CoA Desaturase; Stress; Stroke; System; Talents; Technical Expertise; Testing; Tissues; Training; Universities; Unsaturated Fats; Validation; age related; aging population; base; bioinformatics pipeline; cardioprotection; career; combinatorial; dietary; endoplasmic reticulum stress; fatty acid metabolism; fly; genetic manipulation; genetic variant; genome wide association study; heart function; heart rhythm; high throughput screening; human old age (65+); improved; in vivo; induced pluripotent stem cell; inherited cardiomyopathy; interdisciplinary approach; knock-down; novel; novel therapeutic intervention; novel therapeutics; phospholamban; sarcoplasmic reticulum calcium ATPase; selective expression

Project Summary/Abstract Atrial fibrillation (AF), the most common heart rhythm disorder, is reaching epidemic proportions in the aging population, affecting nearly 33 million people worldwide. The incidence of AF increases with age, with individuals over the age of 65 having a 9% chance of developing this arrhythmia. AF is the leading cause of heart failure and stroke in human populations, and as the average lifespan continues to increase, so will the rates of these disorders. However, the molecular etiology of AF is not well defined and treatment options are limited. Additionally, there is evidence that common substrates link AF with other arrhythmia types and heart disease (e.g. long QT syndrome). Recent research has identified both common genetic variants that increase AF susceptibility in the general population and rare genetic variants linked to AF, suggesting that AF is likely a multifactorial disease whose etiology involves network(s) of interacting genetic variants. Resolving these complex interactions modulating cardiac function in AF is impractical in mammalian systems, but approachable using Drosophila genetics. Drosophila provide an advantage in unraveling the largely unknown genetic regulators of heart dysfunction due to the reduced genetic redundancy and high degree of conservation in the underlying pathways and cellular mechanisms. A subset of AF-associated candidate genes likely interact in a combinatorial manner with age and diet to cause cardiac arrhythmicity. Preliminary screens of candidate AF-related genes in both the fly heart and in human induced pluripotent stem cell atrial-like cardiomyocytes (hiPSC-ACMs) have identified a network of genes that suggests interactions between stearoyl-CoA desaturase (SCD) and two AF-associated genes, KCNA5 and phospholamban (PLN). SCD, a key lipid metabolic enzyme, is known to disrupt sarcoplasmic reticulum calcium ATPase pump (SERCA) activity, however, a KCNA5-SCD-SERCA-PLN network has not been well demonstrated in cardiac tissue. Cardiac phenotyping of interactions found in AF networks in both model systems will identify novel and likely conserved genetic pathways, providing novel therapeutic strategies. Sanford Burnham Prebys (SBP) is an environment that is highly supportive of research and collaborative interdisciplinary approaches, with extensive shared resources providing investigators with both cutting-edge equipment and technical expertise. Dr. Kezos has already mastered a number of complementary scientific concepts and approaches that he is using to address his research questions. Additionally, the Ocorr Laboratory is staffed with talented postdoctoral fellows and staff scientists who will be of assistance to Dr. Kezos during the research training. With the proposed training in the hiPSC model system, bioinformatics pipelines and CRISPR-Cas9 gene editing, Dr. Kezos will be well equipped to launch an impactful and independent research career to investigate the genetics of cardiomyopathies. The proposed research strategy and training plan will accelerate Dr. Kezos towards becoming an independent investigator with a research/teaching track position at a university.

项目摘要/摘要 心房颤动（AF）是最常见的心律障碍，在衰老中达到流行病 人口影响全球近3300万人。 AF的发生率随着年龄的增长而增加 超过65岁以上，有9％的心律失常的机会。 AF是心力衰竭的主要原因 人口中的中风，并且随着平均寿命继续增加，这些寿命也会增加 疾病。但是，AF的分子病因没有很好地定义，治疗方案受到限制。 此外，有证据表明，普通底物与其他心律不齐类型和心脏病联系起来 （例如长QT综合征）。最近的研究已经确定了增加AF的两种常见遗传变异 与AF相关的普通人群和罕见遗传变异的敏感性，这表明AF可能是一种 多因素疾病的病因涉及相互作用遗传变异的网络。解决这些 在哺乳动物系统中，调节AF中心脏功能的复杂相互作用是不切实际的，但平易近人 使用果蝇遗传学。果蝇在揭示未知的遗传调节剂方面提供了优势 心脏功能障碍由于遗传冗余降低和基础途径中的高度保护 和细胞机制。与AF相关的候选基因的子集可能以组合方式相互作用 年龄和饮食会引起心律不齐。两者中与AF相关的候选基因的初步筛选 心脏和人类诱导的多能干细胞心房样心肌细胞（HIPSC-ACM）已经鉴定 基因网络暗示了stearoyl-COA去饱和酶（SCD）与两个AF相关的相互作用 基因，KCNA5和磷脂（PLN）。 SCD是一种关键的脂质代谢酶，已知会破坏肌质 但是，网状钙ATPase泵（SERCA）活性，但是，KCNA5-SCD-SERCA-PLN网络尚未 在心脏组织中得到很好的证明。两种模型中AF网络中发现的相互作用的心脏表型 系统将确定新颖的遗传途径，提供新颖的治疗策略。桑福德 Burnham Prebys（SBP）是一个高度支持研究和协作跨学科的环境 方法，大量共享资源为调查人员提供了尖端设备和 技术专长。 Kezos博士已经掌握了许多互补的科学概念， 他用来解决他的研究问题的方法。此外，Ocorr实验室还配备 才华横溢的博士后研究员和员工科学家，他们将在研究期间为Kezos博士提供帮助 训练。随着HIPSC模型系统，生物信息学管道和CRISPR-CAS9的拟议培训 基佐斯博士的基因编辑将有能力发起影响力和独立的研究职业 研究心肌病的遗传学。拟议的研究策略和培训计划将加速 Kezos博士成为大学的独立研究员，并在大学担任研究/教学轨道职位。