Hox genes in murine reproduction

小鼠生殖中的 Hox 基因

基本信息

批准号：
6637261
负责人：
KENNETH Howard WONG
金额：
$ 13.47万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-08 至 2004-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Homeobox-containing (Hox) genes encode transcriptional factors that regulate cellular positioning and differentiation in the mammalian embryo. Targeted disruptions of specific mouse Abdominal B (AbdB)-related Hox genes have resulted in abnormal female reproductive tract development as well as sterility. The targeted disruption of AbdB-related Hox genes, however, assumes a role for these AbdB-related Hox genes in the function of the adult reproductive system. Specifically, the abnormal development and differentiation of the reproductive system produced by targeted disruptions of AbdB-related Hox genes may interfere with correct interpretation of adult reproductive tract physiology. Furthermore, the genetic regulation between the various AbdB-related Hox genes in the developing mouse female reproductive system has not been previously examined. The applicant's objective is to demonstrate that mouse AbdB-related Hox genes are critical in regulating female reproductive system development and function. To accomplish this objective, three specific aims are presented: 1) Inducible gene targeted disruption of Hoxa10 and Hoxa11 genes in the murine model will be developed; 2) Adult reproductive function will be examined in the induced Hoxa10 and Hoxa11 female mutants and characterized at the gross and cellular level; 3) Candidate molecular components will be studied in the same induced female mutants compared to normal females; and 4) Hox gene regulation of female reproductive tract development will be determined through combinations of targeted Hox disruptions. The overall long-term goal is to elucidate the genetic regulation critical in murine female reproductive tract development and function. Inducible knockouts are an innovative approach in investigating gene disruption in an adult animal. Dr. Capecchi's development of gene targeting and his laboratory's continuing Hox genetic investigations provide a fertile environment to complete this proposal. This puts the applicant in a unique position in having the capacity to conduct the entire spectrum of basic studies that will be required for this proposal. The applicant expects that his results will help guide future studies in human reproductive system function and will ultimately impact on the field of reproductive biology. Under the direction of Dr. Mario Capecchi at the University of Utah, Dr. Kenneth Wong is in a unique position to learn and conduct contemporary gene targeting and genetic investigations. The NICHD Mentored Scientist Clinical Development Award will provide the candidate with the opportunity to develop into a future independent investigator.

描述（由申请人提供）：含同源物的（HOX）基因编码调节细胞定位和分化的转录因子在哺乳动物胚胎中。特定小鼠腹部B的靶向破坏（ABDB）相关的HOX基因导致女性生殖道异常发展和不育。 ABDB相关HOX的目标破坏但是，基因在这些与ABDB相关的HOX基因中的作用成人生殖系统的功能。具体而言，异常生殖系统的开发和分化与ABDB相关的HOX基因的有针对性破坏可能会干扰正确成人生殖道生理学的解释。此外，各种ABDB相关HOX基因之间的遗传调节发育中的小鼠女性生殖系统先前尚未检查。申请人的目标是证明小鼠ABDB相关的HOX基因对于调节女性生殖系统的发展至关重要功能。为了实现这一目标，提出了三个具体目标： 1）诱导基因靶向鼠类Hoxa10和Hoxa11基因的破坏模型将开发； 2）将检查成人生殖功能诱导的Hoxa10和Hoxa11女性突变体，并在总体上进行特征和细胞水平； 3）候选分子成分将在与正常女性相比，相同的诱导女性突变体； 4）HOX基因女性生殖道发育的调节将通过目标HOX中断的组合。总体长期目标是阐明鼠雌性生殖道关键的遗传调节发展和功能。诱导型敲除是研究基因的一种创新方法成年动物的破坏。 Capecchi博士的基因靶向发展他的实验室继续进行的HOX遗传研究提供了肥沃的完成此建议的环境。这使申请人处于独特之处具有进行整个基本范围的能力的位置该提议需要的研究。申请人期望他的结果将有助于指导未来的人类生殖系统研究功能并最终会影响生殖生物学领域。在犹他大学的马里奥·凯西（Mario Capecchi）博士的指导下，博士肯尼思·王（Kenneth Wong）处于学习和进行当代基因的独特位置靶向和遗传研究。 NICHD指导的科学家临床发展奖将为候选人提供发展的机会进入未来的独立调查员。