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 根据生殖生物学培训计划，我从伊利诺伊大学获得了博士学位。在此程序中 在学生和教师之间进行了广泛的互动和讨论。这 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， 并写自己的建议。我的课程专注于生殖生理学，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。在我博士学位之前 幸运的是在三个备受推崇的实验室工作的研究重点从分子生物学到 病理学的人群遗传学。 2003年，我接受了基本电生理学的简短博士后培训。我休息一下 从2004年至2009年的研究到抚养两个孩子。在这段时间里，我将科学文献保持不变 并为研究Alpha 7整合素在斑点开发和Embyonic中的作用做出了贡献 在我的业余时间。我非常错过了研究，并且很有动力返回。我最近有 开始与Iain Buxton博士合作。巴克斯顿博士是一位非常成功的科学家 怀孕期间的子宫功能。 Buxton博士将医学知识的罕见结合，对细节的关注， 和愿景。我们的讨论激发了本提案中提出的思想，我想不出更好的心理 项目。内华达大学医学院的教师因其在 平滑肌生理。他们对平滑肌生理的了解是我背景的完美完成 在分子和细胞生物学以及繁殖的生理学中。在该奖项的修订阶段，我将 学习肌肉力学和电生理学的新实验技能，这将为巨大的效果提供令人兴奋的结果 早产问题。因此，内华达大学是一个理想的机构，可以实现我的职业目标 成为一名独立研究员。我在生殖生理学方面的全面培训以及广泛的 分子生物学，细胞生物化学和最近平滑肌力学的培训具有唯一 我准备调查人类早产期间整合素蛋白行动的令人兴奋且高度相关的话题 劳动。从长远来看，我想获得教师任命并指导基础研究 更好地了解早产劳动以及如何预防劳动。这个奖项可以让我从博士后转移 任命教师的职位。我希望能进一步了解分子的劳动归纳调节 等级。医学院的药理学系的预约理想情况下，我可以确定 药理学剂停止早产。 怀孕期间，劳动的发作取决于子宫肌层从静止的激活 收缩状态。子宫收缩的倡议需要激活内分泌和拉伸引起的 信号通路。拉伸引起的途径的基础机制刚刚开始是 阐明的，但是最近的数据表明，焦点粘附激酶（FAK）在术语人体术语中被激活 组织，整联蛋白参与的有力指标（Li等，2009）。 FAK-ERK途径的激活强烈建议 整联蛋白受体参与是肌层收缩所必需的。因为已证明整联蛋白可以发挥关键作用 在平滑肌收缩力中的角色，我假设至少一个整联蛋白异二聚体对于肌量表至关重要 收缩力。我将确定存在哪些整联蛋白亚基和/或在术语孕妇中更新 肌层并确定单个整联蛋白亚基是否调节人子宫组织的拉伸诱导收缩。 我将创建一个诱导的鼠标模型，在该模型中，整联蛋白„ 1可以在子宫肌层中阻塞1个。 怀孕。我将使用这些小鼠来确定是否损失1整联蛋白是否会降低子宫内膜收缩力。 体外伸展，改变下游信号通路或导致后期劳动。我还将检验以下假设 子宫中增强的整联蛋白-ERK激活有助于早产。我将比较相关的表达 与术语子宫相比 下游FAK-ERK激活在前和后人肌层中发生了变化。定义整合素 - 调节拉伸诱导子宫肌层激活的介导的信号通路将具有重要的 对早产和学期劳动的影响。