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） 候选人是一名符合委员会资格的儿科医生，拥有博士学位。在分子中 遗传学，正在追求遗传学方面的奖学金。 她有着长久以来 对疾病和畸形的机制感兴趣，尤其是 关于心脏。 她从事相关的临床和研究 培训的长期目标是促进对知识的理解 人类发育的遗传和分子机制，特别是心脏发育 畸形和先天性心脏病。 该提案提供了一种机制 为了实现更直接的职业目标，扩大候选人的 基因调控领域的研究背景 胚胎学，从而结合临床和研究兴趣。 此举的目标 提案是确定 Zic3（一种锌指转录）的功能 身体模式形成的因素，特别是中胚层和左右 轴规格和差异化。 未能正确建立 体型和左右不对称是先天性畸形的重要原因 畸形，包括复杂的先天性心脏缺陷。 Zic3是第一个 与人体部位结合识别的基因（左右轴） 异常，这些个体的异常范围是 与 Zic3 在早期胚胎模式中发挥广泛作用一致。 Zic3 在身体模式中的功能研究将通过 Zic3无效突变体和过表达ZIC3的转基因小鼠的分析 中胚层。 这些小鼠将具有表型和分子特征。 通过分析对已知调节基因表达模式的影响 左右不对称，Zic3将被置于分子信号传导内 负责启动和维持左右身体模式的级联 形成。 利用靶向 Zic3 cDNA 进行错误表达分析 与人类谱系中发现的突变相对应的突变将产生小鼠 人类畸形模型并允许表型与 功能蛋白结构域。 建立和定义 Zic3 的作用 左右轴的形成和中胚层的规范将导致改善 了解胚胎模式及其对人类的重要性 畸形。 该提案将在以下环境中进行： 该系以其小鼠遗传学和发育胚胎学而闻名 贝勒医学院分子与人类遗传学博士。 通过一个 监督研究、科学交流和选定的相结合 在此环境中完成课程作业，候选人将获得培训 必须转变为独立调查员。