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: 10576323
• 负责人: James Kezos
• 金额: $ 7.61万
• 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/10576323
• 关键词: Acceleration; 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; Fibrosis; General Population; Generations; Genes; Genetic; Genetic Predisposition to Disease; Heart; Heart Atrium; Heart Diseases; Heart failure; High Fat Diet; Homeostasis; Human; Incidence; Individual; Laboratories; Link; Lipids; Long QT Syndrome; Longevity; Measures; Mediating; Metabolic; Modeling; Molecular; Myocardial dysfunction; Obesity; Organ; Pathogenesis; Pathway interactions; Persons; Phenotype; Phospholipids; Population; Positioning Attribute; Postdoctoral Fellow; Potassium Channel; Predisposition; Production; Pump; Quality of life; Research; Research Personnel; Research Training; Resource Sharing; Risk Factors; Role; Scientist; Small Interfering RNA; Stearoyl-CoA Desaturase; Stress; Stroke; System; Talents; Technical Expertise; Testing; Therapeutic; Tissues; Training; Universities; Unsaturated Fats; Validation; age related; aging population; bioinformatics pipeline; cardioprotection; career; combinatorial; dietary; endoplasmic reticulum stress; fatty acid metabolism; fly; gene interaction; gene network; gene regulatory network; 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; synergism

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.

项目概要/摘要 心房颤动（AF）是最常见的心律失常，在老龄化中已达到流行病的程度 影响全球近 3300 万人。房颤的发病率随着年龄的增长而增加， 65岁以上的人有9%的机会出现这种心律失常。 AF 是心力衰竭的主要原因 人口中的中风和中风，随着平均寿命的不断延长，这些疾病的发生率也会增加 失调。然而，房颤的分子病因学尚未明确，治疗选择也有限。 此外，有证据表明常见底物将 AF 与其他心律失常类型和心脏病联系起来 （例如长 QT 综合征）。最近的研究发现了两种常见的增加房颤的基因变异 一般人群的易感性以及与 AF 相关的罕见遗传变异，表明 AF 可能是一种 其病因涉及相互作用的遗传变异网络的多因素疾病。解决这些 调节 AF 心脏功能的复杂相互作用在哺乳动物系统中不切实际，但可行 使用果蝇遗传学。果蝇在解开很大程度上未知的遗传调节因子方面提供了优势 由于遗传冗余减少和潜在途径的高度保守而导致心脏功能障碍 和细胞机制。 AF 相关候选基因的一个子集可能以组合方式与 年龄和饮食引起心律失常。两种果蝇中候选 AF 相关基因的初步筛选 心脏和人诱导多能干细胞心房样心肌细胞 (hiPSC-ACM) 已鉴定出 基因网络表明硬脂酰辅酶 A 去饱和酶 (SCD) 和两种 AF 相关酶之间存在相互作用 基因、KCNA5 和受磷蛋白 (PLN)。 SCD 是一种关键的脂质代谢酶，已知会破坏肌浆 网状钙 ATP 酶泵 (SERCA) 活性，然而，KCNA5-SCD-SERCA-PLN 网络尚未被研究 在心脏组织中得到了很好的证明。两种模型中 AF 网络中发现的相互作用的心脏表型 系统将识别新颖且可能保守的遗传途径，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跨学科协作的环境 方法，拥有广泛的共享资源，为研究人员提供尖端设备和 技术专长。 Kezos 博士已经掌握了许多互补的科学概念，并且 他用来解决他的研究问题的方法。此外，Ocorr 实验室还配备了 才华横溢的博士后研究员和工作人员科学家将在研究期间为 Kezos 博士提供帮助 训练。通过 hiPSC 模型系统、生物信息学管道和 CRISPR-Cas9 的拟议培训 基因编辑，Kezos 博士将有能力开展有影响力的独立研究生涯 研究心肌病的遗传学。拟议的研究战略和培训计划将加速 Kezos 博士致力于成为一名独立调查员，并在大学担任研究/教学职位。