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(房颤)是最常见的心律失常，随着年龄的增长，房颤的流行程度越来越高。 人口，影响到全世界近3300万人。房颤的发病率随着年龄的增长而增加，在个体中 65岁以上的人患这种心律失常的几率为9%。房颤是心力衰竭的主要原因 和中风，随着平均寿命的持续增加，这些疾病的发病率也会增加 精神错乱。然而，房颤的分子病因尚未明确，治疗选择有限。 此外，有证据表明，常见的底物将房颤与其他类型的心律失常和心脏病联系起来。 (如QT间期延长综合征)。最近的研究已经确定了两种常见的增加房颤的基因变异 普通人群中的易感性和与房颤相关的罕见遗传变异，表明房颤可能是一种 病因涉及相互作用的遗传变异网络的多因素疾病(S)。解决这些问题 在哺乳动物系统中，复杂的相互作用调节房颤的心脏功能是不切实际的，但可以接近 利用果蝇的基因。果蝇在解开基本上未知的基因调控因子方面提供了一个优势 由于基因冗余减少和潜在通路高度保守而导致的心脏功能障碍 和细胞机制。房颤相关候选基因的子集可能以组合方式与 年龄和饮食导致心律失常。两种果蝇房颤相关候选基因的初步筛选 心脏和在人类诱导的多能干细胞心房样心肌细胞(hiPSC-acms)中发现了一种 提示硬脂酰辅酶A脱饱和酶(SCD)与两个房颤相关基因相互作用的基因网络 基因，KCNA5和磷蛋白(PLN)。SCD是一种关键的脂代谢酶，已知可以破坏肌浆 然而，KCNA5-SCD-SERCA-PLN网络尚未形成 在心脏组织中得到了很好的证明。两种模型中房颤网络相互作用的心脏表型 系统将识别新的和可能保守的遗传途径，提供新的治疗策略。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，以广泛的共享资源为调查人员提供尖端设备和 技术专长。凯佐斯博士已经掌握了一些互补的科学概念和 他正在用来解决他的研究问题的方法。此外，Ocorr实验室还配备了 有才华的博士后研究员和科学家，他们将在研究期间为Kezos博士提供帮助 训练。拟议在HiPSC模型系统、生物信息学管道和CRISPR-CAS9方面的培训 基因编辑，凯佐斯博士将做好充分准备，开始一项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快 凯佐斯博士希望成为一名独立研究员，在一所大学担任研究/教学跟踪职位。