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）：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。在该计划中，学生和教职员工之间进行了相当大的互动和讨论。 RBTP教师鼓励学生非常质疑，形成自己的假设，设计自己的实验并编写自己的建议。 我的课程专注于生殖生理学，但还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，我很幸运地在三个备受推崇的实验室中工作，研究重点是从分子生物学到人群遗传学再到病理学。 2003年，我接受了基本电生理学的简短博士后培训。在2004年至2009年之间，我从研究中休息了两个孩子。在这段时间里，我保持了科学文献的最新状态，并有助于研究Alpha 7整合素在业余时间在胎盘发育和胚胎血管化中的作用。我非常错过了研究，并且很有动力返回。我最近开始与Iain Buxton博士合作。巴克斯顿博士是一位非常成功的科学家，在怀孕期间的子宫功能研究方面有很长的记录。巴克斯顿博士拥有医学知识，对细节和视力的罕见结合。我们的讨论激发了本提案中提出的想法，我想不出这个项目的更好的导师。 内华达大学医学院的教师因其在平滑肌生理方面的专业知识而广受认可。他们对平滑肌生理的了解是我在分子和细胞生物学方面的背景以及繁殖生理学的完美补充。 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，这将为早产的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，可以进一步成为我的职业目标，成为一名独立研究员。我在生殖生理学方面的全面培训，结合了分子生物学，细胞生物化学以及最近平滑肌肉力学的广泛培训，使我唯一地准备了我在人类早产和后劳动期间对整合素蛋白作用的令人兴奋且高度相关的主题。从长远来看，我想获得一项教师任命，并指导基础研究，这将使对早产劳动以及如何预防劳动有更好的了解。该奖项将使我从博士后职位转移到教师任命。我希望能够进一步了解分子水平的劳动归纳的调节。医学院的药理学系的任命理想情况下，我可以确定药理学剂来停止早产。 在怀孕期间，劳动的发作取决于从静止状态到收缩状态的子宫肌层的激活。子宫收缩的开始需要激活内分泌和拉伸诱导的信号通路。 拉伸诱导途径的基础机制才刚刚开始阐明，但是最近的数据表明，局部肌肌层组织的局灶性粘附激酶（FAK）被激活，这是整联蛋白参与的强烈指标（Li等人，2009年）。 FAK-ERK途径的激活强烈表明肌层收缩需要整联蛋白受体接合。由于已显示整联蛋白在平滑肌收缩性中起关键作用，因此我假设至少一种整联蛋白异二聚体对于肌层收缩性至关重要。 我将确定存在哪些整联蛋白亚基和/或在术语孕妇人肌层中上调，并确定单个整联蛋白亚基是否调节人子宫组织中的拉伸诱导的收缩。 我将创建一个可诱导的小鼠模型，其中整联蛋白21在怀孕期间可以阻塞子宫肌层。我将使用这些小鼠来确定21个整联蛋白的损失是否会降低子宫内膜收缩力，以响应体外伸展，改变下游信号通路或导致后期劳动。我还将检验以下假设：在子宫中增强的整联蛋白-ERK激活有助于早产。我将比较与术语子宫相比，与术语子宫相比，从前和后人子宫的组织切片中相关整联蛋白的表达，并确定下游FAK-ERK激活是否在前期和后期的人肌层中改变了。 定义调节拉伸诱导子宫肌层激活的整合介导的信号通路将对治疗早产和后期劳动具有重要意义。 公共卫生相关性：怀孕期间的劳动发作取决于子宫收缩的开始。这项研究将确定整联蛋白蛋白是否控制子宫收缩，以及在早产或妊娠后怀孕的情况下这些蛋白质是否改变。