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：
8190303
负责人：
Heather R Burkin
金额：
$ 10.79万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8190303
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)Embryo 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

DESCRIPTION (provided by applicant): 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 embryonic 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 possesses 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 21 production can be blocked in the uterine myometrium during pregnancy. I will use these mice to determine if loss of 21 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. PUBLIC HEALTH RELEVANCE: During pregnancy the onset of labor depends on the initiation of uterine contractions. This study will determine if integrin proteins control uterine contraction and if these proteins are altered in cases of preterm labor or in post-term pregnancies.

描述（由申请人提供）：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。在这个项目中，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，并撰写自己的提案。我的课程主要集中在生殖生理学，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群体遗传学再到病理学。 2003年，我接受了基础电生理学的简短博士后培训。 2004 年至 2009 年间，为了抚养两个孩子，我暂停了研究工作。在此期间，我不断了解最新的科学文献，并利用业余时间参与研究 α7 整合素在胎盘发育和胚胎血管形成中的作用。我非常怀念研究，并且非常有动力回来。我最近开始与伊恩·巴克斯顿博士一起工作。巴克斯顿博士是一位非常成功的科学家，在怀孕期间子宫功能方面有着长期的研究记录。巴克斯顿医生罕见地集医学知识、对细节的关注和远见卓识于一身。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来完成该项目。内华达大学医学院的教师因其在平滑肌生理学方面的专业知识而受到广泛认可。他们对平滑肌生理学的了解是对我在分子和细胞生物学以及生殖生理学方面的背景的完美补充。在该奖项的指导阶段，我将学习肌肉力学和电生理学方面的新实验技能，这将为解决早产这一巨大问题提供令人兴奋的结果。因此，内华达大学是一个理想的机构，可以帮助我进一步实现成为独立研究员的职业目标。我在生殖生理学方面的全面培训与分子生物学、细胞生物化学以及最近的平滑肌力学方面的广泛培训相结合，使我为研究人类早产和足月产后令人兴奋且高度相关的整合素作用主题做好了独特的准备。从长远来看，我希望获得教职并指导基础研究，以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职位晋升为教员。希望对引产在分子水平上的调控有更深入的了解。医学院药理学系的预约将使我能够理想地找到阻止早产的药物。在怀孕期间，临产的开始取决于子宫肌层从静止状态到收缩状态的激活。子宫收缩的启动需要内分泌和拉伸诱导的信号通路的激活。拉伸诱导途径的分子机制刚刚开始被阐明，但最近的数据表明，粘着斑激酶 (FAK) 在足月人类子宫肌层组织中被激活，这是整合素参与的一个强有力的指标 (Li et al., 2009) 。 FAK-ERK 通路的激活强烈表明整合素受体的参与是子宫肌层收缩所必需的。由于整合素已被证明在平滑肌收缩性中发挥着关键作用，因此我假设至少一种整合素异二聚体对于子宫肌层收缩性至关重要。我将确定足月妊娠人类子宫肌层中存在和/或上调哪些整合素亚基，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，怀孕期间子宫肌层中整合素 21 的产生可以被阻断。我将使用这些小鼠来确定 21 整合素的缺失是否会降低体外拉伸反应中的子宫肌层收缩力、改变下游信号通路或导致过期分娩。我还将检验子宫内整合素-ERK 激活增强导致早产的假设。我将比较足月子宫和足月子宫组织切片中相关整合素的表达，并确定足月子宫和足月子宫中下游 FAK-ERK 激活是否发生改变。定义调节子宫肌层拉伸诱导激活的整合素介导的信号通路将对治疗早产和足月产后产生重要影响。公共卫生相关性：怀孕期间临产的开始取决于子宫收缩的开始。这项研究将确定整合素蛋白是否控制子宫收缩，以及这些蛋白是否在早产或过期妊娠的情况下发生改变。