Integrin Regulation of Stretch-Activated Myometrial Signaling During Pregnancy an

怀孕期间拉伸激活的子宫肌层信号的整合素调节

• 批准号: 8687806
• 负责人: Heather R Burkin
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687806
• 关键词: Actins; Animals; Appointment; Attention; Award; Basic Science; Binding; Biochemistry; Blocking Antibodies; Cellular biology; Child; Complement; Data; Developmental Biology; Doctor of Philosophy; Early Diagnosis; Early treatment; Electrophysiology (science); Endocrine; Extracellular Matrix; Faculty; Focal Adhesion Kinase 1; Focal Adhesions; Genetic; Goals; Human; Illinois; In Vitro; Individual; Institution; Integrins; Knowledge; Labor Onset; Laboratories; Lead; Learning; Literature; Mechanics; Mediating; Medical; Mentors; Methods; Microbiology; Molecular; Molecular Biology; Molecular Target; Molecular and Cellular Biology; Mus; Muscle; Myometrial; Myosin ATPase; Nevada; Pathology; Pathway interactions; Pharmacology; Phase; Phosphorylation; Physiology; Placentation; Play; Population Genetics; Positioning Attribute; Pregnancy; Premature Labor; Process; Production; Protein Isoforms; Proteins; Regulation; Reproduction; Reproductive Biology; Reproductive Physiology; Research; Research Ethics; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Smooth Muscle; Stretching; Students; Testing; Time; Tissues; Training; Training Programs; Universities; Uterine Contraction; Uterus; Vascularization; Vision; Work; Writing; career; design; dimer; human ITGA7 protein; insight; medical schools; mouse model; myometrium; post-doctoral training; pregnant; prevent; programs; receptor; research study; response; skills

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.

项目摘要 我在伊利诺伊大学的生殖生物学培训项目下获得了博士学位。在这个项目中， 是学生和教师之间的大量互动和讨论，具有广泛的研究重点。 的 RBTP教师鼓励学生非常质疑，形成自己的假设，设计自己的实验， 写他们自己的提案 我的课程集中在生殖生理学，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。在我读博士之前， 我有幸在三个备受推崇的实验室工作，研究重点从分子生物学到 人口遗传学和病理学2003年，我接受了基础电生理学的博士后培训。我休息了一下 从2004年到2009年的研究，以提高两个孩子。在这段时间里，我一直在阅读最新的科学文献。 并对研究α 7整合素在胎盘发育和胚胎发育中的作用做出了贡献。 在我的业余时间进行血管化。我非常想念研究，我非常有动力回来。我最近 开始与伊恩·巴克斯顿博士合作 Buxton博士是一位非常成功的科学家，在以下领域有着长期的研究记录： 怀孕期间的子宫功能。 巴克斯顿医生拥有罕见的医学知识，对细节的关注， 和远见。我们的讨论激发了这份提案中提出的想法，我想不出更好的导师了 项目 内华达州大学医学院的教师因其在以下方面的专业知识而得到广泛认可： 平滑肌生理学他们的平滑肌生理学知识是对我的背景的完美补充 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 早产的问题。因此，内华达州的大学是一个理想的机构，其中进一步我的职业目标 成为一名独立的研究员。我在生殖生理学方面的全面训练， 在分子生物学、细胞生物化学和最近的平滑肌力学方面的训练， 准备我调查令人兴奋的和高度相关的主题整合素行动在人类早产和足月后 劳动 从长远来看，我想获得一个教师的任命，并指导基础研究，这将导致一个 更好地了解早产以及如何预防早产。这个奖项将使我从一个博士后 一个教师职位的任命。希望能从分子水平上对引产的调控有进一步的认识 水平在医学院药理学系的一个职位最好能让我找出 药物治疗以阻止早产。 妊娠期间，分娩的开始依赖于子宫肌层从静止期到静止期的激活。 收缩状态 子宫收缩的启动需要激活内分泌和牵张诱导的 信号通路 拉伸诱导途径的分子机制才刚刚开始 然而，最近的数据表明，在足月人子宫肌层中，粘着斑激酶（FAK）被激活， 组织，整联蛋白结合的强指标（Li等， 2009年）。 FAK-ERK通路的激活强烈表明 子宫肌层收缩需要整联蛋白受体结合。因为整合素已被证明发挥关键作用 在平滑肌收缩中的作用，我假设至少有一种整合素异源二聚体对子宫肌层 收缩性 我将确定哪些整合素亚单位存在和/或上调，在足月妊娠的人 子宫肌层，并确定是否个别整联蛋白亚单位调节牵张诱导的收缩在人类子宫组织。 我将创建一个诱导型小鼠模型，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 我将使用这些小鼠来确定是否1整合素的缺失会降低子宫肌层的收缩力， 在体外拉伸，改变下游信号通路，或导致过期分娩。我还将检验一个假设， 子宫内整合素-ERK活化增强有助于早产。 我将比较相关的表达 与足月子宫相比，在来自早产和足月人子宫的组织切片中的整合素，并确定 下游FAK-ERK活化在足月前和足月后人子宫肌层中改变。 定义整合素- 调节牵张诱导的子宫肌层激活的介导的信号传导途径将具有重要的 对治疗早产和过期分娩的意义。