Genetics and Structure of Trabecular Myocardium in Development and Disease

发育和疾病中小梁心肌的遗传学和结构

• 批准号: 9764455
• 负责人: Rima Arnaout
• 金额: $ 18.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764455
• 关键词: Ablation; Adult; Advisory Committees; Atrial Natriuretic Factor; Back; Bioinformatics; Biological Models; California; Cardiac Myocytes; Cardiovascular system; Cells; Cessation of life; Code; Data; Development; Developmental Biology; Disease; ERBB2 gene; Embryo; Environment; Gene Expression Profiling; Genes; Genetic Structures; Goals; Growth; Heart; Heart Diseases; Heart Injuries; Heart failure; Heritability; Histologic; Human; Infrastructure; Inherited; Injury; Knock-out; Lead; Left; Left ventricular non-compaction; Maintenance; Mentors; Mentorship; Messenger RNA; Methods; Modeling; Myocardial; Myocardial dysfunction; Myocardium; Natriuretic Peptides; Natural regeneration; Partner in relationship; Pathogenesis; Pathway interactions; Pattern; Peptide Signal Sequences; Physicians; Population; Process; Program Development; Research; Research Institute; Research Personnel; Ribosomes; Role; San Francisco; Scientist; Synapses; System; Techniques; Testing; Thick; Tissues; Training; Transgenic Organisms; Translating; Universities; Ventricular; Ventricular Arrhythmia; Ventricular Remodeling; Work; Zebrafish; base; cardiac muscle disease; cardiac regeneration; cardiogenesis; career; career development; congenital heart disorder; design; developmental genetics; experimental study; genome analysis; heart function; heart imaging; in vivo; injured; insight; knock-down; loss of function; notch protein; novel; overexpression; peptide A; programs; promoter; public health relevance; reconstitution; regenerative; skills training; success; tool; transcriptome sequencing

 DESCRIPTION (provided by applicant): This proposal describes a five-year mentored career development program designed to prepare Dr. Rima Arnaout for her long-term career goal to be an independent investigator. This proposal builds upon Dr. Arnaout's background as a cardiologist and a basic scientist in cardiovascular development by providing training in bioinformatics approaches to genome analysis as well as other techniques critical to success of the research approach. Dr. Shaun Coughlin, Director of the Cardiovascular Research Institute at the University of California, San Francisco and an expert in cardiovascular research, will serve as the primary mentor for this project. Dr. Coughlin's mentorship is part of a training plan that includes formal mentorship by an advisory committee of leaders in cardiovascular development, formal coursework and skills training, and a research plan that will provide rigorous training in developmental biology and genetics. This work will be supported in an outstanding environment for cardiovascular research rich with the intellectual and programmatic support and infrastructure necessary for the development of an independent physician-scientist. In preliminary work, Dr. Arnaout has created tools that can be used to study the thickening and remodeling of the ventricular myocardium to form trabeculae. Trabeculation is an essential process in normal heart development and function, and several congenital and heritable heart diseases are characterized by hypo- or hyper- trabeculation. The overall goal of the studies proposed is therefore to illuminate the mechanisms governing initiation of trabeculation in development and regeneration. This goal will be achieved by exploiting specific strengths of the zebrafish model systems and by using natriuretic peptide A (nppa) as a tool to mark and manipulate trabeculated myocardium. Dr. Arnaout will first test the hypothesis that nppa participates in the initiation of trabeculation during development by performing knockout and expression studies in zebrafish. To interrogate roles of endocardial-myocardial contact in trabeculation in vivo, Dr. Arnaout will use the GFP Reconstitution Across Synaptic Partners (GRASP) system. She will then test the hypothesis that the regenerative growth in adult zebrafish hearts arises from nppa-positive cells when trabeculae are selectively injured. Compared to prior models for heart injury, Dr. Arnaout's model for heart injury more closely approximates the most common kind of human heart injury. Finally, Dr. Arnaout will extend her analysis of trabeculated vs non-trabeculated myocardium, using RNA-Seq to compare gene programs in trabecular myocardium at baseline and in regeneration and discover novel genes and pathways to investigate across vertebrate systems. By identifying the mechanisms responsible for the initiation and maintenance of trabeculation in development and after heart injury, the work proposed will provide valuable insight into the pathogenesis of several congenital heart diseases and also lay important groundwork for mastering cardiac regeneration after injury.

 描述（由应用程序提供）：该提案描述了一项为期五年的职业发展计划，旨在为Rima Arnaout博士做准备，以使其长期职业目标成为独立研究员。这项建议是基于Arnaout博士作为心脏病专家和心血管发展的基础科学家的基础，该建议是通过为基因组分析的生物信息学方法提供培训，以及对研究方法成功至关重要的其他技术。加州大学旧金山心血管研究所的主任肖恩·科夫林（Shaun Coughlin）博士，心血管研究专家，将作为该项目的主要心理。 Coughlin博士的心态是一项培训计划的一部分，其中包括由心血管发展，正式课程和技能培训领导者的正式心态，以及将在初步工作中提供严格培训的研究计划，Arnaout博士创建了工具，可以使用该工具，可用于研究心肌的增厚和形成Trabeculae的增厚。小梁是正常心脏发育和功能中的重要过程，几种先天性和可遗传的心脏病的特征在于低于小精神或超小径。因此，提出的研究的总体目的是阐明有关小梁在发育和再生中的启动的机制。通过利用斑马鱼模型系统的特定强度以及使用Natriaretic肽A（NPPA）作为标记和操纵小径的心肌来实现该目标。 Arnaout博士将首先检验以下假设：NPPA通过在斑马鱼中进行敲除和表达研究在发育过程中参与小偷的倡议。为了询问心内膜心肌接触在体内小梁中的作用，Arnaout博士将在突触伙伴（GRASP）系统中使用GFP重建。然后，她将检验以下假设：成年斑马鱼心的再生生长在选择性受伤时由NPPA阳性细胞产生。与先前的心脏损伤模型相比，Arnaout博士的心脏损伤模型更接近最常见的人类心脏损伤。最后，Arnaout博士将使用RNA-Seq扩展对小径与未经牵引的心肌的分析，以比较基线和再生中小梁心肌中的基因程序，并发现新的基因和途径在跨脊椎动物系统之间进行研究。通过确定负责和维持在发育中和心脏损伤后的小偷的机制，提出的工作将为多种先天性心脏病的发病机理提供宝贵的见解，并为掌握损伤后掌握心脏再生的重要扎根。

项目成果

Best practices for authors of healthcare-related artificial intelligence manuscripts.

• DOI: 10.1038/s41746-020-00336-w
• 发表时间: 2020
• 期刊: NPJ digital medicine
• 影响因子: 15.2
• 作者: Kakarmath S;Esteva A;Arnaout R;Harvey H;Kumar S;Muse E;Dong F;Wedlund L;Kvedar J
• 通讯作者: Kvedar J

Minimum information about clinical artificial intelligence modeling: the MI-CLAIM checklist.

• DOI: 10.1038/s41591-020-1041-y
• 发表时间: 2020-09
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Norgeot B;Quer G;Beaulieu-Jones BK;Torkamani A;Dias R;Gianfrancesco M;Arnaout R;Kohane IS;Saria S;Topol E;Obermeyer Z;Yu B;Butte AJ
• 通讯作者: Butte AJ

Proposed Requirements for Cardiovascular Imaging-Related Machine Learning Evaluation (PRIME): A Checklist: Reviewed by the American College of Cardiology Healthcare Innovation Council.

• DOI: 10.1016/j.jcmg.2020.07.015
• 发表时间: 2020-09
• 期刊: JACC. Cardiovascular imaging
• 作者: Sengupta PP;Shrestha S;Berthon B;Messas E;Donal E;Tison GH;Min JK;D'hooge J;Voigt JU;Dudley J;Verjans JW;Shameer K;Johnson K;Lovstakken L;Tabassian M;Piccirilli M;Pernot M;Yanamala N;Duchateau N;Kagiyama N;Bernard O;Slomka P;Deo R;Arnaout R
• 通讯作者: Arnaout R