A Gata456 Pipeline of Discovery

Gata456 发现管道

• 批准号: 10543782
• 负责人: Todd R Evans
• 金额: $ 81.07万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543782
• 关键词: Adult; Alleles; Animals; Area; Atrial Heart Septal Defects; Biological Models; Biology; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cell Therapy; Cells; Code; Development; Differentiation Antigens; Disease model; Disparate; Endocardium; Epicardium; Epigenetic Process; GATA4 gene; Generations; Genes; Genetic; Goals; Growth; Heart; Heart Diseases; Human; Hypertrophy; Individual; Lead; Life; Location; Mesoderm; Morphogenesis; Mutation; Myocardial; Myocardium; Natural regeneration; Organ; Phenotype; Positioning Attribute; Research Personnel; Specific qualifier value; Syndrome; Tetralogy of Fallot; Therapeutic; Tissues; Tube; Ventricular Septal Defects; Zebrafish; bicuspid aortic valve; cardiogenesis; cardioprotection; cellular development; familial dilated cardiomyopathy; gain of function; human embryonic stem cell; human pluripotent stem cell; loss of function; novel; progenitor; programs; therapeutic target; transcription factor

Three highly related genes, Gata4, Gata5, and Gata6 (referred to here as Gata456) regulate essentially every aspect of cardiac biology, from generation of precardiac mesoderm, specification and differentiation of endocardial, epicardial, and myocardial progenitors, heart tube formation, growth and morphogenesis, septation and valve formation, cardioprotection and hypertrophy, and regeneration. How the three genes regulate the spatial, temporal, and tissue-specific genetic and epigenetic networks that underlie all of these disparate programs is poorly understood. Furthermore, mutations in each of the genes have individually been associated with human cardiomyopathies, including atrial and ventricular septal defects, tetralogy of Fallot, bicuspid aortic valve syndrome, and familial dilated cardiomyopathy. Other transcription factor genes, and some terminal differentiation markers are known to be regulated by Gata456, but a major gap in understanding is the identify of the key target genes that control intermediary functions such as lineage specification, growth, morphogenesis, and cardio-protection. We propose a new program as a “Pipeline of Discovery” to identify these downstream genes and probe their function in cardiogenesis and cardiac biology. The overall goal is to define the function of each Gata456 gene throughout development and adult life in various cardiac tissues including endocardium, myocardium, and epicardium. We seek to break the code for how the relative timing and location of expression for each gene impacts cell fate and survival, and organ morphogenesis and function. Complementary model systems exploit specific advantages and resolve species-specific distinctions: the zebrafish for understanding cardiogenesis including morphogenesis, and human pluripotent stem cells for understanding human cell identity and disease modeling. We have compiled a “toolbox” of zebrafish and hESC lines and an expert team of investigators to facilitate a comprehensive analysis of gain-and loss-of-function phenotypes, with a strong track record for such analyses and discovery of novel downstream targets. A breakthrough is needed to understand how Gata456 controls all the various aspects of cardiogenesis. We are finally in a position to define this code, by a systematic manipulation of each factor in different developmental and tissue contexts, leading to discovery of specific key downstream target genes that carry out these diverse functions. This project will not directly develop therapeutics for cardiac disease, but it will likely enhance development of cellular therapies. Chiefly, it will break ground beyond current descriptions of regulatory networks in two areas: 1) Defining the impact for loss or gain of individual Gata456 alleles at specific developmental stages and in specific tissues to precisely define functions in developing animals (zebrafish) and human cells (derived from human pluripotent cells). 2) Identifying the key downstream Gata456 target genes that are responsible for stage and tissue-specific functions, recognizing these as “lead hit” therapeutic targets for treating cardiac disease. !

三个高度相关的基因 Gata4、Gata5 和 Gata6（此处称为 Gata456）基本上调控着每一个基因。 心脏生物学方面，从心前中胚层的产生、规范和分化 心内膜、心外膜和心肌祖细胞、心管形成、生长和形态发生， 分隔和瓣膜形成、心脏保护和肥大以及三个基因如何再生。 调节所有这些基础的空间、时间和组织特异性遗传和表观遗传网络 此外，人们对不同基因的突变知之甚少。 与人类心肌病相关，包括房间隔缺损、室间隔缺损、法洛四联症、 二叶式主动脉瓣综合征和家族性扩张型心肌病，以及其他转录因子基因。 已知一些终末分化标记物受 Gata456 调节，但理解上存在重大差距 是控制中间功能（例如谱系规范、生长、 我们提出了一个新计划作为“发现管道”来识别。 这些下游基因并探讨它们在心脏发生和心脏生物学中的功能。 定义每个 Gata456 基因在整个发育和成年生活中在各种心脏组织中的功能 包括心内膜、心肌和心外膜，我们寻求打破相对时间的密码。 每个基因的表达和位置都会影响细胞的命运和存活，以及器官的形态发生和 互补模型系统利用特定优势并解决物种特定的差异： 斑马鱼用于了解心脏发生（包括形态发生），而人类多能干细胞用于了解 了解人类细胞身份和疾病模型我们编制了斑马鱼和 hESC 的“工具箱”。 线和专家调查小组，以促进对功能获得和丧失的全面分析 表型，在此类分析和发现新下游靶点 A 方面拥有良好的记录。 需要突破来了解 Gata456 如何控制心脏发生的各个方面。 最终能够通过系统地操纵不同发育阶段的每个因素来定义这个代码 和组织背景，导致发现执行这些不同的特定关键下游靶基因 该项目不会直接开发心脏病的治疗方法，但可能会增强功能。 首先，它将突破目前监管描述之外的领域。 网络有两个领域：1) 定义特定 Gata456 等位基因损失或增加的影响 发育阶段和特定组织，以精确定义发育中动物（斑马鱼）的功能 和人类细胞（源自人类多能细胞） 2) 识别关键的下游 Gata456 靶点。 负责阶段和组织特异性功能的基因，将其识别为“先导”治疗 治疗心脏病的目标。 ！

项目成果

Cardiovascular Small Heat Shock Protein HSPB7 Is a Kinetically Privileged Reactive Electrophilic Species (RES) Sensor.

心血管小热休克蛋白 HSPB7 是一种动力学特权反应亲电物质 (RES) 传感器。

• DOI: 10.1021/acschembio.7b00925
• 发表时间: 2018
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Surya,SanjnaL;Long,MarcusJC;Urul,DanielA;Zhao,Yi;Mercer,EmilyJ;EIsaid,IslamM;Evans,Todd;Aye,Yimon
• 通讯作者: Aye,Yimon

Cardiomyocytes recruit monocytes upon SARS-CoV-2 infection by secreting CCL2.

• DOI: 10.1016/j.stemcr.2021.07.012
• 发表时间: 2021-09-14
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Yang L;Nilsson-Payant BE;Han Y;Jaffré F;Zhu J;Wang P;Zhang T;Redmond D;Houghton S;Møller R;Hoagland D;Carrau L;Horiuchi S;Goff M;Lim JK;Bram Y;Richardson C;Chandar V;Borczuk A;Huang Y;Xiang J;Ho DD;Schwartz RE;tenOever BR;Evans T;Chen S
• 通讯作者: Chen S

Tet Proteins Regulate Neutrophil Granulation in Zebrafish through Demethylation of socs3b mRNA.

• DOI: 10.1016/j.celrep.2020.108632
• 发表时间: 2021-01-12
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Banks KM;Lan Y;Evans T
• 通讯作者: Evans T

Epigenetic Regulation of Cardiac Development and Disease through DNA Methylation.

通过 DNA 甲基化对心脏发育和疾病进行表观遗传调控。

• 发表时间: 2019
• 期刊: Journal of life sciences (Westlake Village, Calif.)
• 作者: Lan,Yahui;Evans,Todd
• 通讯作者: Evans,Todd

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.

• DOI: 10.1161/circresaha.121.320518
• 发表时间: 2022-04
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Han Y;Zhu J;Yang L;Nilsson-Payant BE;Hurtado R;Lacko LA;Sun X;Gade AR;Higgins CA;Sisso WJ;Dong X;Wang M;Chen Z;Ho DD;Pitt GS;Schwartz RE;tenOever BR;Evans T;Chen S
• 通讯作者: Chen S