Genetic Determinants of Outflow Tract Morphogenesis

流出道形态发生的遗传决定因素

• 批准号: 8271372
• 负责人: C. Geoffrey Burns
• 金额: $ 43.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271372
• 关键词: Adult; Angioblast; Animal Model; Applications Grants; Arteries; Binding Proteins; Biological Models; Birds; Cardiac; Cardiac Myocytes; Cardiovascular Abnormalities; Cardiovascular system; Cell Proliferation; Cells; Cellular biology; Cessation of life; Complement; Congenital Heart Defects; Defect; Development; Elastin; Embryo; Embryonic Heart; Endocardium; Evaluation; Exhibits; Genes; Genetic; Genetic Determinism; Goals; Heart; Heart Diseases; Human; Investigation; Label; Lateral; Ligands; Location; Mesoderm; Molecular; Molecular Chaperones; Molecular Profiling; Morbidity - disease rate; Morphogenesis; Mus; Myocardial; Myocardium; Neural Crest; Newborn Infant; Pathway interactions; Phenotype; Population; Proteins; Public Health; Regenerative Medicine; Reporting; Research; Role; Signal Transduction; Smooth Muscle; Specific qualifier value; Stem cells; Testing; Time; Transcript; Transforming Growth Factors; Tube; Ventricular; Vertebrates; Western World; Work; Zebrafish; aortic arch; base; congenital heart disorder; design; malformation; mortality; mouse model; mutant; novel; progenitor; receptor; regenerative therapy; research study; therapeutic target; transcription factor

The long-term goal of our work is to reduce the enormous public health burden caused by heart diseases, both congenital and adult, through a better understanding of vertebrate cardiac progenitor cell biology. Defects in a recently-characterized population of cardiac progenitor cells, the secondary heart field (SHF), have been shown to cause conotruncal malformations in avian and mouse species suggesting that, by analogy, human congenital heart defects can arise from defects in SHF. Currently, SHF research is conducted exclusively in avian and mouse model systems. We provide preliminary evidence that the SHF is conserved in zebrafish, a model organism with unique attributes that will undoubtedly complement studies in higher vertebrates. Specifically, we have demonstrated that a protein required for transforming growth factor ¿ (TGF¿) signaling, latent TGF¿ binding protein 3 (LTBP3), not only marks the zebrafish SHF, but is also required for the contributions made by SHF progenitors to the embryonic heart. As a result, embryos devoid of LTBP3 transcripts exhibit significant reductions in ventricular lineages (cardiomyocytes and endocardial cells), outflow tract smooth muscle, and aortic arch angioblasts and arteries. The proposed experiments are designed to test the hypotheses that LTBP3+ cells represent the functional equivalent of the SHF, that TGF¿ signaling is required for SHF development, and that LTBP3 function is genetically downstream of fgf8, an archetypal SHF gene in higher vertebrates. In the long run, these studies will potentially highlight novel genetic causes of human congenital heart disease as well as illuminate potential therapeutic targets for directed differentiation of resident or embryonic cardiac progenitor cells for use in regenerative therapies.

我们工作的长期目标是减轻心脏病造成的巨大公共卫生负担 通过更好地了解脊椎动物心脏祖细胞生物学缺陷，研究先天性和成人性。 最近表征的心脏祖细胞群，即次级心脏区域（SHF），已被 已被证明会导致鸟类和小鼠的圆锥干畸形，这表明，通过类比，人类 先天性心脏缺陷可能是由 SHF 缺陷引起的。目前，SHF 研究仅在以下国家进行。 我们提供了鸟类和小鼠模型系统中 SHF 在斑马鱼中保守的初步证据。 具有独特属性的模型生物无疑将补充高等脊椎动物的研究。 具体来说，我们已经证明转化生长因子所需的蛋白质 ¿ (TGF¿) 信号传导， 潜伏性TGF¿结合蛋白 3 (LTBP3)，不仅标记斑马鱼 SHF，而且也是 SHF 祖细胞对胚胎心脏的贡献因此，胚胎缺乏 LTBP3。 转录物表现出心室谱系（心肌细胞和心内膜细胞）、流出物显着减少 所提出的实验旨在测试束平滑肌、主动脉弓成血管细胞和动脉。 假设 LTBP3+ 细胞代表 SHF 的功能等同物，即 TGF¿信号传递是 SHF 发育所需，并且 LTBP3 功能在遗传上是 fgf8（一种典型 SHF）的下游 从长远来看，这些研究将有可能突显高等脊椎动物的新遗传原因。 人类先天性心脏病以及阐明定向分化的潜在治疗靶点 用于再生疗法的驻留或胚胎心脏祖细胞。