Development of Xenopus as a Model to Study Congenital Heart Disease

开发非洲爪蟾作为研究先天性心脏病的模型

• 批准号: 7666876
• 负责人: ANN F RAMSDELL
• 金额: $ 10.39万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666876
• 关键词: Ablation; Address; Affect; Anterior; Antibodies; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiac conduction system; Cell Lineage; Cells; Complement; Complex; Computer Systems Development; Congenital Heart Defects; Data; Defect; Development; Developmental Process; Dextrans; Dyes; EFRAC; Echocardiography; Educational process of instructing; Embryo; Embryonic Development; Exhibits; Faculty; Failure; Foundations; Functional disorder; Funding; Future; Genes; Genetic; Grant; Handedness; Heart; Heart Atrium; Heart Rate; Heart Septal Defects; Histologic; Independent Scientist Award; Individual; Investigation; Isomerism; Joints; Label; Lasers; Left; Life; Maps; Mesoderm; Methodology; Modeling; Molecular; Morphogenesis; Neural Crest; Nitrogen; Optics; Organ; Pathway interactions; Pattern; Physiologic pulse; Physiology; Play; Population; Positioning Attribute; Process; Productivity; Progress Reports; Rana; Research; Research Personnel; Role; Services; Signal Pathway; Situs Inversus; Solid; Source; Stroke Volume; Syndrome; System; Techniques; Testing; Time; Tissue Grafts; Tissues; Travel; United States National Institutes of Health; Universities; Ventricular; Vertebrates; Visceral; Work; Xenopus; Xenopus laevis; abstracting; base; cardiogenesis; congenital heart disorder; dextran; heart rhythm; innovation; malformation; meetings; molecular marker; novel; tool; xenopus development

DESCRIPTION (provided by applicant): The objective of this proposal is to substantially increase protected research time in order to boost productivity on a currently funded R01 (and its pending renewal) while positioning the candidate to successfully compete for a second major grant (i.e. a new R01 or a project on a programmatic grant). The candidate holds a joint faculty position between two state universities located ~120 miles apart. Travel, teaching and service obligations leave 45% time available for research. Support by a K02 award would release the candidate from most teaching and service assignments, generating 80-95% time over the next five years to be spent exclusively on research. The overall objectives of the candidate's funded R01 and pending renewal are to discover fundamental mechanisms of heart development, and to determine how they are affected by laterality genes during cardiac (dys)morphogenesis. To achieve this, the candidate has established an experimentally-induced heterotaxy model in embryos of the frog, Xenopus laevis. The heterotaxy embryos exhibit abnormal cardiac and visceral organ L-R asymmetries that are accompanied by complex, congenital heart defects (CHDs). Using an innovative cell labeling strategy to produce the first L-R cell lineage map of the vertebrate heart, the candidate discovered that L-R cell lineage composition is anomalous in heterotaxy hearts, and that the L-R lineage defects co-localize with structural CHDs. Based on these results and others, the K02 Aims are to identify in Xenopus the cardiac cell populations that, together with working cardiomyocytes derived from the primary heart fields, build the heart: secondary heart field, cardiac neural crest, and cardiac conduction system. These Aims will be accomplished by spending "minisabbaticals" in leading labs to adapt functional (laser-assisted tissue ablation, echocardiography, optical activation mapping) and additional embryological techniques (caged fluorescent dextrans, tissue grafting) for use in Xenopus. This will be complemented by coursework and participation in professional meetings. Data from the K02 Aims will be used to propose and test novel hypotheses on the role that L-R lineage composition in various cardiac cell populations play in cardiac (dys)morphogenesis. The significance of this work will be to elucidate conserved mechanisms of heart development, which in turn, will identify genes and inductive processes that may cause CHDs if affected by genetic or environmental perturbations. (End of Abstract)

描述(由申请人提供)： 这项提议的目的是大幅增加受保护的研究时间，以提高目前资助的R01(及其即将续期)的生产率，同时定位候选人成功竞争第二个主要赠款(即新的R01或方案赠款上的项目)。这位候选人在相距约120英里的两所州立大学担任联合教职。旅行、教学和服务职责使45%的时间用于研究。K02奖的支持将使候选人从大多数教学和服务任务中解脱出来，在接下来的五年中产生80%-95%的时间专门用于研究。候选人资助的R01和即将更新的总体目标是发现心脏发育的基本机制，并确定它们在心脏(Dys)形态发生过程中如何受到偏侧基因的影响。为了实现这一点，这位候选人在非洲爪蛙的胚胎中建立了一个实验诱导的异质性模型。异位胚胎表现出心脏和内脏器官L-R不对称的异常，并伴有复杂的先天性心脏缺陷(CHD)。使用一种创新的细胞标记策略来制作第一张脊椎动物心脏的L-R细胞谱系图，候选人发现L-R细胞谱系组成在异位心脏中异常，并且L-R谱系缺陷与结构性CHD共存。基于这些结果和其他结果，K02的目的是在非洲爪哇中识别心脏细胞群体，这些细胞与来自初级心脏领域的工作心肌细胞一起构建心脏：次级心脏领域、心脏神经脊和心脏传导系统。这些目标将通过在领先的实验室花费“小休假”来适应功能(激光辅助组织消融、超声心动图、光学激活标测)和额外的胚胎学技术(笼式荧光右旋糖苷、组织移植)来实现。除此之外，还将进行课程作业和参加专业会议。来自K02 AIMS的数据将被用来提出和测试新的假设，即不同心脏细胞群体中的L-R谱系组成在心脏(DYS)形态发生中扮演的角色。这项工作的意义将是阐明心脏发育的保守机制，这反过来将确定如果受到遗传或环境扰动的影响，可能导致CHD的基因和诱导过程。 (摘要结束)