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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我在伊利诺伊大学的生殖生物学培训项目中获得了博士学位。学生和教师之间有大量的互动和讨论，研究重点广泛。 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，并写出他们自己的建议。我的课程集中在生殖生理学上，但也包括在内。在获得博士学位之前，我从事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。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 2003 年，我接受了基础电生理学的短暂博士后培训。从 2004 年到 2009 年的研究中，我一直在研究科学文献。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非常怀念业余时间的血管化研究，并且最近非常有动力回来。开始与 Iain Buxton 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。巴克斯顿博士罕见地结合了医学知识、对细节的关注、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。内华达大学医学院的教师因其在该项目方面的专业知识而受到广泛认可。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，我将在该奖项的指导阶段获得博士学位。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因此，内华达大学是我实现职业目标的理想机构。成为一名独立研究员分子生物学、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，这个奖项将使我能够从博士后转向。我希望进一步了解分子引产的监管。医学院药理学系的预约最适合我来确定。阻止早产的药物。在怀孕期间，临产的开始取决于子宫肌层从静止期到临产期的激活。子宫收缩的启动需要内分泌和拉伸诱导的激活。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）强烈表明 FAK-ERK 通路的激活。整合素受体的参与是子宫肌层收缩所必需的，因为整合素已被证明发挥着关键作用。在平滑肌收缩力中的作用，我发现至少一种整合素异二聚体对于子宫肌层至关重要我将确定足月孕妇中存在和/或上调的整合素亚基。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，其中整合素 ¿ 1 生产过程中可阻止子宫肌层我将使用这些小鼠来确定是否失去了 ¿ 1 整合素降低子宫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。子宫内增强的整合素-ERK 激活有助于早产，我将比较相关的表达。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。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过期分娩的影响。