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.



项目成果

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