Heritable Defects of Human Tooth Development

描述：（由申请人提供）许多脊椎动物器官的发育 依赖于上皮和间充质之间的相互诱导信号。 在这个过程中起重要作用的一类基因是 属于Msx同源盒基因家族。小鼠和人类研究 揭示了MSX沿着其他基因指定了头骨、面部、皮肤和 牙齿发育牙列是牙齿的主要组成部分， 哺乳动物颅面系统，也提供了一个强大的和潜在的一般 器官发育的研究模型。这一点进一步证明， 丰富的信息的遗传层次，运作在早期 牙齿发育（Kratochwil等人，1996; Vaahtokari等人，1996年; Neubiser 等1997; Bei和Maas，1998;综述于Thesleff等，1995年; Maas和 Bei，1997; Thesleff and Sharpe，1997; Peters and flailing，1999）.申请人 已经能够解开部分遗传途径， 使用基因工程Msx 1和/或Msx 2小鼠的牙齿发育 变种人申请人已经能够解开部分遗传途径 负责早期牙齿发育的基因工程Msx 1 和/或Msx 2小鼠突变体。尽管Msx基因调控的信息 通过上位性分析表达，Msx基因调控的下游靶点 以及Msx蛋白控制转录的分子机制 器官发生的调节仍然是未知的。能够进一步拓展自己的 在分子生物学和人类遗传学方面的研究活动，申请人将 寻求一个新的研究方向，试图从基因组的基础上理解 转录谱和分子研究的遗传性疾病 人类牙齿发育作为她以前工作的延续， 了解Msx基因在小鼠和人类颅面发育中的作用， 这项计划的目标是确定参与模式化的新基因， 正常牙齿发育的小鼠，并筛选是否他们的人类 直向同源物含有导致遗传性牙齿疾病的突变 发展 申请人长期以来一直有兴趣了解不同的途径 参与正常的颅面发育，以及如何在不同的 基因破坏了这一过程，而这一过程构成了她的职业目标。功能 基因组学和人类遗传学是新的研究领域， 有吸引力的调查机会，并使申请人能够 成为当代基因组学和分子生物学的独立研究者 遗传学这一职业奖将为她提供科学成熟， 实现职业目标所需的经验。

DESCRIPTION: (provided by applicant) The development of many vertebrate organs depends on reciprocal inductive signaling between epithelium and mesenchyme. One class of genes that play important role during this process are those belonging to the Msx homeobox gene family. Studies in both mouse and humans revealed that MSX along with other genes specify the skull, face, skin and tooth development. The dentition which comprises a major component of the mammalian craniofacial system, also provides a powerful and potentially general model for the study of organ development. This is further demonstrated by the wealth of information on the genetic hierarchies which operate during early tooth development (Kratochwil et al., 1996; Vaahtokari et al., 1996; Neubuser et al. 1997: Bei and Maas, 1998; reviewed in Thesleff et a., 1995; Maas and Bei, 1997; Thesleff and Sharpe, 1997; Peters and flailing, 1999). The applicant has been able to unravel part of the genetic pathway responsible for early tooth development using the genetically engineered Msx1 and/or Msx2 mouse mutants. The applicant has been able to unravel part of the genetic pathway responsible for early tooth development using the genetically engineered Msx1 and/or Msx2 mouse mutants. Despite information about the regulation of Msx gene expression by epistasis analysis, the downstream targets of Msx gene regulation and the molecular mechanisms by which the Msx proteins control transcriptional regulation of organogenesis remain largely unknown. To further expand her research activities in molecular biology and human genetics the applicant will seek a new research direction trying to understand from genome based transcriptional profiling and molecular studies the heritable disorders of human tooth development. As a continuation of her previous work and in order to understand the role of Msx genes in mouse and human craniofacial development, the goal of this proposal is to identify novel genes involved in the patterning of normal tooth development in the mouse and to screen whether their human orthologs contain mutations responsible for heritable disorders of tooth development. The applicant has a long-standing interest to understand the different pathways involved in normal craniofacial development and how mutations in different genes disrupt this process which constitutes her career goal. Functional genomics and human genetics are new research areas that provide extremely attractive opportunities for investigation and will enable the applicant to become an independent investigator in contemporary genomics and molecular genetics. This career award will provide her with scientific maturity and experience required for realizing her career goal.