Zic3 and the Control of Body Pattern Formation

Zic3 和身体模式形成的控制

• 批准号: 6322902
• 负责人: Stephanie M Ware
• 金额: $ 9.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6322902
• 关键词: congenital disorders; developmental genetics; embryogenesis; gene expression; gene mutation; gene targeting; genetic promoter element; genetically modified animals; in situ hybridization; laboratory mouse; lethal genes; mammalian embryology; mesoderm; protein localization; retinoate; transcription factor

DESCRIPTION (provided by applicant) The candidate, a board eligible pediatrician with a Ph.D. in molecular genetics, is pursuing a fellowship in genetics. She has a long-standing interest in the mechanisms underlying disease and malformation, especially with regard to the heart. She has pursued relevant clinical and research training with a long term goal of contributing to the understanding of the genetic and molecular mechanisms of human development, particularly cardiac malformation and congenital heart disease. This proposal provides a mechanism for realizing a more immediate career goal of expanding the candidate's research background in gene regulation to the fields of development and embryology, thus combining clinical and research interests. The goal of this proposal is to identify the function of Zic3, a zinc finger transcription factor, in body pattern formation, specifically in mesoderm and left-right axis specification and differentiation. The failure to properly establish body pattern and left-right asymmetry is an important cause of congenital malformation, including complex congenital heart defects. Zic3 is the first gene identified in conjunction with human situs (left-right axis) abnormalities, and the spectrum of anomalies in these individuals is consistent with Zic3 playing a broad role in early embryonic patterning. Investigation of Zic3 function in body patterning will be undertaken via analyses of Zic3 null mutants and transgenic mice over expressing ZIC3 in mesoderm. These mice will be characterized phenotypically and molecularly. By analyzing the effects on the expression pattern of genes known to regulate left-right asymmetry, Zic3 will be placed within the molecular signaling cascade responsible for initiating and maintaining left-right body pattern formation. Misexpression analyses utilizing targeted Zic3 cDNAs with mutations corresponding to those found in human pedigrees will create mouse models of human malformation and allow correlation of phenotype with functional protein domains. Establishing and defining the role of Zic3 in left-right axis formation and mesoderm specification will lead to an improved understanding of embryonic patterning and its importance in human malformation. This proposal will be undertaken in an environment that is renowned for its mouse genetics and developmental embryology, the Department of Molecular and Human Genetics at Baylor College of Medicine. Through a combination of supervised research, scientific interchange, and selected coursework within this environment, the candidate will obtain the training necessary to transition to an independent investigator.

描述（由申请人提供） 候选人是一名符合博士学位的董事会符合条件的儿科医生。在分子 遗传学，正在追求遗传学研究金。 她有一个长期的 对疾病和畸形的基本机制的兴趣，尤其是 关于心脏。 她从事相关的临床和研究 长期目标的培训是为理解的理解做出贡献 人类发育的遗传和分子机制，尤其是心脏 畸形和先天性心脏病。 该建议提供了一种机制 为了实现扩大候选人的更直接的职业目标 基因调节的研究背景与发展领域 胚胎学，从而结合临床和研究兴趣。 目标的目标 建议是确定ZIC3的功能，锌指转录 因素，身体模式形成，特别是中胚层和左右 轴规范和分化。 无法正确建立 身体模式和左右不对称是先天性的重要原因 畸形，包括复杂的先天性心脏缺陷。 ZIC3是第一个 与人类位点（左右轴）结合识别的基因 这些人的异常和异常的频谱是 与ZIC3一致，在早期胚胎图案中起着广泛的作用。 将通过 ZIC3无效突变体和转基因小鼠在表达ZIC3中的分析 中胚层。 这些小鼠将以表型和分子的形式表征。 通过分析对已知调节基因的表达模式的影响 左右不对称，将ZIC3放置在分子信号中 负责发起和维护左右身体模式的级联 形成。 使用目标ZIC3 cDNA的Misexpression分析 与人类血统中发现的突变会产生鼠标 人类畸形的模型，并允许表型与 功能性蛋白质结构域。 建立和定义ZIC3在 左右轴形成和中胚层规格将导致改进 了解胚胎图案及其在人类中的重要性 畸形。 该建议将在一个环境中进行 该部门以其老鼠遗传学和发育性胚胎学而闻名 贝勒医学院的分子和人类遗传学。 通过一个 监督研究，科学互换和选定的结合 在这种环境中的课程工作，候选人将获得培训 过渡到独立研究者所必需的。