The role of Twisted Gastrulation in Mouse Development

描述(申请人提供)：Petryk医生是明尼苏达大学的儿科内分泌学家。候选人的长期目标是追求主要致力于基础研究的学术生涯。作为一名儿科住院医生和内分泌学研究员，佩特里克医生参与了大量先天畸形和生长障碍患者的护理工作。她对这些健康问题的分子基础的兴趣促使她进行发育生物学的研究培训，以了解它们的发病机制，作为未来可能的治疗干预的基础。Petryk博士培育了扭曲原肠形成(TSG)缺陷小鼠，将作为研究骨骼和神经管发育的分子和细胞机制的模型。这项工作将在迈克尔·奥康纳博士的指导下进行。佩特里克博士还建立了重要的合作关系，这些合作关系将对她的职业发展计划起到重要作用。 TSG最近被认为是一种新的骨形态发生蛋白(BMP)拮抗剂，是无脊椎动物和低等脊椎动物正常胚胎发育所必需的。TSG被认为与另一种细胞外蛋白Chordin(CHD)协同作用，通过阻止BMP2和BMP4与受体的结合来抑制BMP2和BMP4信号。TSG在哺乳动物发育中的作用目前尚不清楚。初步表型分析表明，TSG缺陷小鼠的生长和骨骼缺陷与脊柱裂相似。CHD缺陷小鼠也有骨骼缺陷和异常的神经管图案。比较CHD缺陷小鼠和TSG缺陷小鼠的表型，以及TSG双突变体的产生，将为先天性畸形的分子机制提供新的见解。候选人将追求以下特定目标：1)表征TSG缺陷小鼠骨骼缺陷和生长缺陷的潜在机制；2)通过产生和鉴定TSG；CHD双重突变体，了解TSG与CHD在小鼠胚胎发育中的相互作用。

DESCRIPTION (provided by applicant): Dr. Petryk is a pediatric endocrinologist at the University of Minnesota. The candidate's long-term goal is to pursue an academic career devoted primarily to basic research. As a pediatric resident and an endocrinology fellow, Dr. Petryk was involved in the care of a significant number of patients with congenital malformations and growth disorders. Her interest in the molecular basis of these health problems led her to pursue research training in developmental biology in order to gain understanding of their pathogenesis as a basis for possible therapeutic interventions in the future. Dr. Petryk has generated twisted gastrulation (tsg) deficient mice that will serve as a model to study molecular and cellular mechanisms of skeletal and neural tube development. This work will be carried out under the mentorship of Dr. Michael O'Connor. Dr. Petryk has also established key collaborations that will be instrumental in her career development plan. Tsg has recently been recognized as a new bone morphogenetic protein (BMP) antagonist that is required for normal embryonic development of invertebrate and lower vertebrate species. Tsg is thought to act synergistically with another extracellular protein Chordin (Chd) to inhibit BMP2 and BMP4 signaling by preventing their binding to the receptors. The role of Tsg in mammalian development is currently unknown. Preliminary phenotypic analysis indicates that Tsg-deficient mice have reduced growth and skeletal defects similar to those that occur in spina bifida. Chd-deficient mice also have skeletal defects and abnormal neural tube patterning. The comparison of the phenotypes of mice deficient in Chd versus those deficient in Tsg, and generation of Tsg;Chd double mutants, will offer new insight into the molecular mechanisms of congenital malformations. The candidate will pursue the following specific aims: 1) Characterize the mechanisms underlying the skeletal defects and growth deficiency in Tsg-deficient mice; 2) Understand the interactions between Tsg and Chd in mouse embryonic development by generating and characterizing Tsg;Chd double mutants.