Heritable Defects of Human Tooth Development

描述：(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。 在这一过程中发挥重要作用的一类基因是 属于MSX同源框基因家族。对小鼠和人类的研究 揭示了MSX和其他基因一起指定了头骨、面部、皮肤和 牙齿发育。牙列是牙列的主要组成部分 哺乳动物的头面部系统，也提供了强大和潜在的一般 器官发育研究的模型。这一点进一步体现在 丰富的关于在早期运行的遗传等级的信息 牙齿发育(Kratochwil等人，1996；Vaahtokari等人，1996；Neubuser 等人的研究。1997年：Bei和Maas，1998；在Theesleff et a.，1995中回顾；Maas和 贝，1997；特斯勒夫和夏普，1997；彼得斯和扑翼，1999)。申请人 已经能够解开导致早期遗传途径的一部分 利用基因工程Msx1和/或MSX2小鼠进行牙齿发育 变种人。申请者已经能够解开遗传途径的一部分 使用基因工程Msx1负责早期牙齿发育 和/或MSX2小鼠突变体。尽管有关于MSX基因调控的信息 MSX基因下游调控靶点的上位性分析表达 以及MSX蛋白控制转录的分子机制 器官发生的调控在很大程度上仍不清楚。以进一步扩大她的业务范围 申请人将从事分子生物学和人类遗传学方面的研究活动 从基因组看问题寻求新的研究方向 遗传性疾病的转录图谱和分子研究 人类牙齿发育。作为她之前工作的延续，为了 了解MSX基因在小鼠和人类颅面发育中的作用， 这项提议的目标是识别与图案形成有关的新基因。 小鼠牙齿的正常发育，并筛选它们的人类 同源基因包含导致牙齿遗传性疾病的突变 发展。 申请人对了解不同的途径有着长期的兴趣 参与正常颅面发育以及不同基因突变的不同 基因破坏了这一过程，而这一过程构成了她的职业目标。功能性 基因组学和人类遗传学是新的研究领域，它们为 有吸引力的调查机会，并将使申请人能够 成为当代基因组学和分子科学领域的独立研究者 遗传学。这个职业奖项将为她提供科学上的成熟和 实现她的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.