Zic3 and the Control of Body Pattern Formation

描述(由申请人提供) 候选人是一名符合董事会资格的儿科医生，拥有分子医学博士学位 遗传学，正在寻求遗传学方面的奖学金。她有一个长期的 对疾病和畸形的潜在机制感兴趣，特别是 关于心的问题。她从事过相关的临床和研究。 培训的长期目标是促进对 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。这项提议提供了一种机制 为了实现一个更直接的职业目标，即扩大候选人的 基因调控的研究背景与发展方向 胚胎学，因此结合了临床和研究兴趣。这样做的目的是 建议鉴定Zic3的功能，一个锌指转录 体型形成中的因素，特别是在中胚层和左右 中轴线的规范和区分。未能正确地建立 体型和左右不对称是先天性心脏病的重要原因 畸形，包括复杂的先天性心脏缺陷。Zic3是第一个 与人类部位相关的基因(左右轴) 异常，这些个体的异常范围是 这与Zic3在早期胚胎模式中发挥的广泛作用是一致的。 Zic3在人体造型中的功能研究将通过 Zic3缺失突变体和转基因小鼠过表达ZIC3的分析 中胚层。这些小鼠将进行表型和分子特征的研究。 通过分析对已知调控基因表达模式的影响 左右不对称，Zic3将被放置在分子内的信号传递 负责启动和维持左右身体模式的级联 队形。利用靶向Zic3cDNA进行错义表达分析 与人类谱系中发现的基因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在 左右轴的形成和中胚层的规范将导致改善 对胚胎模式的理解及其在人类中的重要性 畸形。这项提议将在以下环境中进行 该系以小鼠遗传学和发育胚胎学著称 贝勒医学院分子和人类遗传学专业。通过一个 监督研究、科学交流和精选相结合 在这种环境下，应聘者将获得培训 向独立调查员过渡是必要的。

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.