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: 8725213
• 负责人: Heather R Burkin
• 金额: $ 21.83万
• 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/8725213
• 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.

项目概要 我通过生殖生物学培训计划获得了伊利诺伊大学的博士学位。在这个程序中有 学生和教师之间有大量的互动和讨论，研究重点广泛。 这 RBTP 教师鼓励学生勇于质疑，形成自己的假设，设计自己的实验， 并写下自己的建议。 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。在获得博士学位之前，我是 幸运的是能够在三个备受推崇的实验室工作，研究重点从分子生物学到 群体遗传学到病理学。 2003年，我接受了基础电生理学的简短博士后培训。我休息了一下 根据2004年至2009年抚养两个孩子的研究。在此期间，我不断了解最新的科学文献 并为研究 α7 整合素在胎盘发育和胚胎发育中的作用做出了贡献 我在业余时间进行血管化治疗。我非常怀念研究，并且非常有动力回来。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，在以下领域拥有长期的研究记录： 怀孕期间的子宫功能。 巴克斯顿博士罕见地将医学知识、对细节的关注、 和愿景。我们的讨论激发了该提案中提出的想法，我想不出更好的导师了 项目。 内华达大学医学院的教师因其在以下领域的专业知识而受到广泛认可： 平滑肌生理学。他们的平滑肌生理学知识是对我背景的完美补充 分子和细胞生物学以及生殖生理学。 在这个奖项的指导阶段，我将 学习肌肉力学和电生理学方面的新实验技能，这将为巨大的研究提供令人兴奋的结果 早产问题。因此，内华达大学是实现我职业目标的理想机构 成为一名独立研究员。我在生殖生理学方面的全面培训结合了广泛的 分子生物学、细胞生物化学以及最近的平滑肌力学方面的培训具有独特的优势 使我准备好研究人类早产期和产后期间整合素作用的令人兴奋且高度相关的主题 劳动。 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。这个奖项将使我从博士后转为博士后 职位到教员任命。希望对引产的分子调控有进一步的了解 等级。医学院药理学系的预约将使我能够理想地确定 阻止早产的药物。 怀孕期间，临产的开始取决于子宫肌层从静止期到临产期的激活。 收缩状态。 子宫收缩的启动需要内分泌和牵张诱导的激活 信号通路。 拉伸诱导途径的分子机制才刚刚开始被研究 已阐明，但最近的数据表明，粘着斑激酶 (FAK) 在足月人类子宫肌层中被激活 组织，整合素参与的有力指标（Li et al., 2009）。 FAK-ERK 通路的激活强烈表明 子宫肌层收缩需要整合素受体的参与。因为整合素已被证明发挥着关键作用 在平滑肌收缩力中发挥作用，我假设至少一种整合素异二聚体对于子宫肌层至关重要 收缩性。 我将确定足月孕妇中存在哪些整合素亚基和/或哪些整合素亚基上调 子宫肌层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。 我将创建一个诱导小鼠模型，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 1 整合素的缺失是否会降低肌层收缩力 体外拉伸，改变下游信号通路，或导致过期分娩。我还将检验以下假设 子宫内整合素-ERK 激活增强会导致早产。 我会比较相关的表达 与足月子宫相比，足月前和足月后人类子宫组织切片中的整合素，并确定是否 下游 FAK-ERK 激活在早产儿和产后人类子宫肌层中发生改变。 定义整合素 调节子宫肌层拉伸诱导激活的介导信号通路将具有重要意义 对治疗早产和足月产后的影响。