Zic3 and the Control of Body Pattern Formation

描述（由申请人提供） 候选人是一名合格的儿科医生，拥有博士学位。in molecular 遗传学，正在攻读遗传学奖学金。 她有一个长期 对疾病和畸形的潜在机制感兴趣，特别是 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 人类发育的遗传和分子机制，特别是心脏 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， 基因调控的研究背景，以发展和 胚胎学，从而结合临床和研究兴趣。 这个目标 我们的建议是确定Zic 3的功能，Zic 3是一个锌指转录因子， 因子，在体型形成中，特别是在中胚层和左右 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，包括复杂的先天性心脏缺陷。 Zic3是第一个 与人体部位相关的基因（左右轴） 异常，这些个体的异常谱是 这与Zic 3在早期胚胎形成中发挥广泛作用相一致。 Zic 3在身体模式中的功能的研究将通过以下方式进行： Zic3无效突变体和过表达ZIC3的转基因小鼠的分析 中胚层 将对这些小鼠进行表型和分子表征。 通过分析对已知调控基因表达模式的影响， 左右不对称，Zic 3将被放置在分子信号传导内， 负责启动和维持左右身体模式的级联 阵 利用靶向Zic3 cDNA的错误表达分析， 对应于在人类谱系中发现的那些突变将产生小鼠 人类畸形模型，并允许表型与 功能蛋白质结构域 建立和定义Zic3在以下方面的作用 左右轴形成和中胚层特化将导致改善的 了解胚胎模式及其对人类的重要性 畸形 这项建议将在一个环境中进行， 以其小鼠遗传学和发育胚胎学而闻名， 贝勒医学院的分子和人类遗传学教授。 通过 结合监督研究，科学交流，并选择 在这种环境中，候选人将获得培训 需要过渡到独立调查员。

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.