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: 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
• 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

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）：我在伊利诺伊大学生殖生物学培训项目下获得博士学位。在这个项目中，学生和教师之间有相当多的互动和讨论，有广泛的研究重点。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，并撰写自己的提案。 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 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。在此期间，我一直与科学文献保持联系，并在业余时间参与研究α 7整合素在胎盘发育和胚胎血管形成中的作用。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。巴克斯顿博士是一位非常成功的科学家，在怀孕期间的子宫功能研究方面有着悠久的历史。巴克斯顿博士拥有罕见的医学知识，对细节的关注和远见的结合。我们的讨论激发了这个提案中提出的想法，我想不出这个项目的更好的导师。 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分子和细胞生物学以及生殖生理学背景的完美补充。 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，这将为早产的巨大问题提供令人兴奋的结果。因此，内华达州大学是一个理想的机构，可以进一步实现我的职业目标，成为一名独立研究人员。我在生殖生理学方面的全面培训结合了分子生物学，细胞生物化学和最近的平滑肌力学方面的广泛培训，使我能够独特地研究人类早产和足月分娩期间整合素作用的令人兴奋和高度相关的主题。从长远来看，我想获得一个教师职位，并指导基础研究，这将导致更好地了解早产和如何预防它。这个奖项将使我从博士后职位转移到教师职位。希望能在分子水平上对引产的调控有进一步的认识。在医学院药理学系的一个职位最好能让我找到阻止早产的药物。 在妊娠期间，分娩的开始依赖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刚刚开始阐明，然而最近的数据已经显示，在足月人子宫肌层组织中，粘着斑激酶（FAK）被激活，这是整联蛋白接合的强指标（Li et al.，2009年）。FAK-ERK通路的激活强烈提示整合素受体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中发挥关键作用，我假设至少有一个整合素异二聚体将是必不可少的子宫肌层收缩。 我将确定哪些整合素亚基在足月妊娠人子宫肌层中存在和/或上调，并确定单个整合素亚基是否调节人子宫组织中牵张诱导的收缩。 我将创建一个诱导型小鼠模型，其中整合素21的产生可以在妊娠期间在子宫肌层中被阻断。我将使用这些小鼠来确定是否21整合素的丢失降低了子宫肌层对体外牵拉的收缩力，改变了下游信号通路，或导致过期分娩。我也将检验子宫内整合素-ERK激活增强导致早产的假设。我将比较早产和足月人子宫组织切片中相关整合素的表达，并确定早产和足月人子宫肌层中下游FAK-ERK激活是否发生改变。 确定整合素介导的调节牵张诱导的子宫肌层激活的信号通路将对治疗早产和过期分娩具有重要意义。 公共卫生相关性：妊娠期间分娩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，以及这些蛋白质在早产或过期妊娠的情况下是否发生变化。