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（这里称为Gata456）基本上控制着每一种基因

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