Integrin Regulation of Stretch-Activated Myometrial Signaling During Pregnancy an

项目总结 我在伊利诺伊大学生殖生物学培训项目下获得了博士学位。在这个节目中， 在学生和教职员工之间有相当大的互动和讨论，研究重点广泛。这个 RBTP教师鼓励学生非常质疑，形成他们自己的假设，设计他们自己的实验， 然后写出他们自己的提案。我的课程集中在生殖生理学上，但也包括 生物化学和细胞生物学、发育生物学、遗传学、微生物学和研究伦理学。在攻读博士学位之前，我是 有幸在三个享有盛誉的实验室工作，研究重点从分子生物学到 从群体遗传学到病理学。2003年，我接受了基础电生理学方面的短期博士后培训。我休息了一下 在2004至2009年间进行的养育两个孩子的研究。在这段时间里，我了解了最新的科学文献。 并参与了研究α7整合素在胎盘发育和胚胎发育中的作用的工作 在我的业余时间做血管重建术。我非常怀念研究，我非常有动力回来。我最近有过 开始与伊恩·巴克斯顿博士合作。巴克斯顿博士是一位非常成功的科学家，在 妊娠期间的子宫功能。巴克斯顿博士罕见地将医学知识、对细节的关注 和远见。我们的讨论激发了这项提议中提出的想法，我想不出有什么比这更好的导师了 项目。内华达大学医学院的教职员工因其在 平滑肌肉生理学。他们在平滑肌生理学方面的知识是对我背景的完美补充 在分子和细胞生物学以及生殖生理学方面。在这个奖项的指导阶段，我将 学习肌肉力学和电生理学的新实验技能，这将为巨大的 早产问题。因此，内华达大学是我实现职业目标的理想学校 成为一名独立研究人员。我在生殖生理学方面的全面训练与广泛的 在分子生物学、细胞生物化学和最近的平滑肌力学方面的培训是独一无二的 让我准备好研究人类早产和足月后整合素作用这一令人兴奋且高度相关的话题 劳力。从长远来看，我希望获得一份教职，并指导基础研究，这将导致 更好地了解早产以及如何预防早产。这一奖项将使我从博士后 一份教职任命的职位。我希望在分子水平上对引产的调节有进一步的了解。 水平。在医学院这里的药理学系的预约将是我理想的位置，以确定 用于阻止早产的药剂。 在妊娠期间，分娩的开始依赖于子宫肌层从静止状态到 收缩状态。子宫收缩的开始需要内分泌和牵张诱导的激活。 信号通路。牵张诱导通路背后的分子机制才刚刚开始 然而，最近的数据表明，在人类子宫肌层中，粘着斑激酶(FAK)被激活 组织，整合素参与的强烈指示器(Li等人，2009年)。FAK-ERK通路的激活强烈提示 整合素受体参与是子宫肌层收缩所必需的。因为整合素已经被证明起着关键作用 在平滑肌收缩中的作用，我假设至少有一个整合素异源二聚体对子宫肌层是必不可少的 伸缩性。我将确定哪些整合素亚单位存在和/或在足月怀孕的人中上调 并确定单个整合素亚基是否调节人类子宫组织中拉伸诱导的收缩。 我将创建一个可诱导的小鼠模型，在该模型中，整合素1的产生可以在子宫肌层中被阻断 怀孕了。我将用这些小鼠来确定1整合素的缺失是否会降低子宫肌层的收缩能力 在体外拉伸，改变下游信号通路，或导致产后分娩。我还将检验这一假设 子宫中整合素-ERK的激活增强有助于早产。我会比较一下相关的表达方式 人足月子宫和足月子宫组织切片中整合素的比较 FAK-ERK下游激活在足月前和足月后人类子宫肌层中发生变化。定义整合素- 调节拉伸诱导的子宫肌层激活的中介信号通路将具有重要的作用 治疗早产和足月后分娩的意义。

PROJECT SUMMARY I received my PhD from the University of Illinois under the Reproductive Biology Training Program. In this program there is considerable interaction and discussion among the students and faculty with a wide range of research focuses. The RBTP faculty encourages students to be very questioning, form their own hypotheses, design their own experiments, and write their own proposals. My coursework was concentrated on reproductive physiology but also included biochemistry and cell biology, developmental biology, genetics, microbiology, and research ethics. Prior to my PhD I was fortunate to work in three highly regarded laboratories with research focuses ranging from molecular biology to population genetics to Pathology. In 2003 I received brief postdoctoral training in basic electrophysiology. I took a break from research between 2004 and 2009 to raise two children. During this time I kept current with the scientific literature and contributed to work investigating the role of the alpha 7 integrin in placental development and embyonic vascularization in my spare time. I have missed research very much and am highly motivated to return. I have recently begun working with Dr. Iain Buxton. Dr. Buxton is a highly successful scientist with a long track record of research in uterine function during pregnancy. Dr. Buxton posesses a rare combination of medical knowledge, attention to detail, and vision. Our discussions stimulated the ideas presented in this proposal and I cannot think of a better mentor for this project. The faculty here at the University of Nevada School of Medicine is widely recognized for their expertise in smooth muscle physiology. Their knowledge of smooth muscle physiology is the perfect complement for my background in molecular and cellular biology and the physiology of reproduction. During the mentored phase of this award I will learn new experimental skills in muscle mechanics and electrophysiology that will provide exciting results for the huge problem of preterm labor. Therefore, the University of Nevada is an ideal institution in which to further my career goals to become an independent researcher. My comprehensive training in Reproductive Physiology combined with extensive training in molecular biology, cellular biochemistry, and more recently smooth muscle mechanics have uniquely prepared me to investigate the exciting and highly relevant topic of integrin action during human preterm and post-term labor. In the longer term I would like to obtain a faculty appointment and to direct basic research that will lead to a better understanding of preterm labor and how to prevent it. This award would allow me to move from a postdoctoral position to a faculty appointment. I hope to gain further insights into the regulation of labor induction at the molecular level. An appointment in the Pharmacology Department here at the medical school would ideally situate me to identify pharmacological agents to halt preterm labor. During pregnancy the onset of labor is dependent on activation of the uterine myometrium from the quiescent to the contractile state. The initiation of uterine contractions requires the activation of both endocrine and stretch-induced signaling pathways. The molecular mechanisms underlying the stretch-induced pathway are just beginning to be elucidated, however recent data have shown that Focal Adhesion Kinase (FAK) is activated in term human myometrial tissue, a strong indicator of integrin engagement (Li et al., 2009). Activation of the FAK-ERK pathway strongly suggests integrin receptor engagement is required for myometrial contraction. Because integrins have been shown to play pivotal roles in smooth muscle contractility, I hypothesize at least one integrin heterodimer will be essential to myometrial contractility. I will determine which integrin subunits are present and/or upregulated in term pregnant human myometrium and determine if individual integrin subunits regulate stretch-induced contraction in human uterine tissue. I will create an inducible mouse model in which integrin ¿1 production can be blocked in the uterine myometrium during pregnancy. I will use these mice to determine if loss of ¿1 integrin decreases myometrial contractility in response to stretch in vitro, alters downstream signaling pathways, or results in post-term labor. I will also test the hypothesis that enhanced integrin-ERK activation in the uterus contributes to preterm labor. I will compare the expression of relevant integrins in tissue sections from pre-term and post-term human uterus compared to term uterus and determine if downstream FAK-ERK activation is altered in pre-term and post-term human myometrium. Defining the integrin- mediated signaling pathways that regulate stretch induced activation of the uterine myometrium will have important implications for treating preterm and post term labor.