A 3D IN VITRO DISEASE MODEL OF ATRIAL CONDUCTION

心房传导 3D 体外疾病模型

• 批准号: 10228624
• 负责人: David Terry Curiel
• 金额: $ 106.55万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228624
• 关键词: 3-Dimensional; Address; Adenoviruses; Adult; Age; Arrhythmia; Atrial Fibrillation; Benchmarking; Biological Models; Biology; CRISPR interference; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cells; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Disease; Disease model; Drug Screening; Elderly; Electrophysiology (science); Elements; Fibrinogen; Gene Delivery; Gene Expression; Genes; Genome; Goals; Health Care Costs; Heart; Heart Atrium; Human; In Vitro; Incidence; Methods; Microfluidics; Modeling; Myocardium; NOTCH1 gene; Nodal; Organ; Patients; Pharmaceutical Preparations; Phase; Plant Roots; Population; Prevalence; Production; Regulator Genes; Regulatory Pathway; Reproducibility; Resources; Risk Factors; Signal Transduction; Solid; Source; Specificity; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Tissue Microarray; Tissues; Validation; base; cohort; cost effective; design; drug discovery; drug efficacy; efficacy study; efficacy testing; epigenome; epigenomics; human model; human old age (65+); human tissue; in vitro Model; induced pluripotent stem cell; innovation; knock-down; medication safety; microphysiology system; model development; novel; novel strategies; novel therapeutic intervention; precision medicine; preclinical efficacy; programs; safety testing; side effect; therapeutic candidate; therapeutic target; transcription factor; transcriptome

PROJECT SUMMARY Nearly 1 in 10 adults over the age of 65 in the U.S. suffer from atrial fibrillation (AF) leading to approximately $6 billion annually in healthcare costs. Because advanced age is a primary risk factor for developing AF, the overall incidence is expected to rise steadily over the coming decades as our population ages. Current therapeutic interventions have remarkably poor efficacy and/or untoward side effects due in large part to our inability to target the root cause of the disease and provide specificity for the atria and the patient. The central objective of this proposal is to create and validate a robust 3D microphysiological model of abnormal human atrial conduction using induced pluripotent stem cells from the patient. The model will simulate important elements of AF, such as conduction velocity, and develop novel therapeutic strategies that employ adenoviral delivery of gene interference (CRISPRi) that target altered gene regulatory pathways as the source of AF. We will accomplish this objective by completing the following specific aims: 1) characterize the transcriptome, epigenome, and electrophysiology of adult human atrial cardiomyocytes (normal and AF); 2) create a 3D in vitro disease model of human atrial conduction leveraging human iPS cell-derived atrial cardiomyocytes (iPS- aCM) and atrial regulatory gene expression; 3) design and test an adenoviral gene delivery strategy to specifically target atrial (not ventricular or nodal) cardiomyocytes; 4) demonstrate atrial specific adenoviral delivery (SA3) of CRISPRi and gene interference of PITX2 in ex vivo human atrial tissue; and 5) create iPS- aCM and the corresponding in vitro model of atrial conduction from a cohort of normal subjects and patients with AF; characterize drug efficacy and gene delivery in the in vitro models using a panel of existing drugs and our atrial specific adenoviral construct for CRISPR gene interference of PITX2 (SA3). Completing the specific aims will provide a model of human atrial conduction that can be used as a broad platform to understand drug efficacy and safety for diseases such as AF.!

项目摘要 在美国，65岁以上的成年人中有近十分之一患有心房纤颤（AF），导致大约 每年60亿美元的医疗费用。由于高龄是发生AF的主要风险因素， 随？人口老化，整体发病率预期在未来数十年会稳步上升。电流 治疗性干预具有非常差的功效和/或不良的副作用，这在很大程度上是由于我们 无法针对疾病的根本原因并为心房和患者提供特异性。中央 该方案的目的是创建和验证异常人体的鲁棒3D微生理模型 使用来自患者的诱导多能干细胞进行心房传导。该模型将模拟重要的 AF的要素，如传导速度，并开发新的治疗策略， 基因干扰（CRISPRi）的递送，靶向改变的基因调控途径作为AF的来源。 将通过完成以下具体目标来实现该目标：1）表征转录组， 成年人心房心肌细胞（正常和AF）的表观基因组和电生理学; 2）在 利用人iPS细胞衍生的心房心肌细胞（iPS- aCM）和心房调节基因表达; 3）设计和测试腺病毒基因递送策略， 特异性靶向心房（非心室或结）心肌细胞; 4）证实心房特异性腺病毒 在离体人心房组织中CRISPRi的递送（SA 3）和PITX 2的基因干扰;和5）产生iPS- 正常受试者和患者队列的aCM和相应的心房传导体外模型 使用一组现有药物在体外模型中表征药物疗效和基因递送， 我们的心房特异性腺病毒构建体用于PITX 2（SA 3）的CRISPR基因干扰。完成具体的 aims将提供一个人类心房传导的模型，可以作为一个广泛的平台来了解药物。 对AF等疾病的疗效和安全性。

项目成果

Mitigating neutrophil trafficking and cardiotoxicity with DS-IkL in a microphysiological system of a cytokine storm.

在细胞因子风暴的微生理系统中用 DS-IkL 减轻中性粒细胞运输和心脏毒性。

• DOI: 10.1039/d2lc01070d
• 发表时间: 2023
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Shirure,VenkteshS;Yechikov,Sergey;Shergill,BhupinderS;Dehghani,Tima;Block,AntonV;Sodhi,Harkanwalpreet;Panitch,Alyssa;George,StevenC
• 通讯作者: George,StevenC

Organotypic stromal cells impact endothelial cell transcriptome in 3D microvessel networks.

• DOI: 10.1038/s41598-022-24013-y
• 发表时间: 2022-11-28
• 期刊: Scientific reports
• 影响因子: 4.6