Lipid Bodies and Prostaglandin Production in Labor

该建议描述了一个严格的五年培训计划，旨在促进发展一个 生殖医学的独立学术生涯。主要研究者已完成博士后研究 在俄亥俄州州立大学（OSU）的围产期研究实验室（LPR）获得奖学金。在此基础上 经验，该计划旨在通过学徒制扩展特定的科学技能， 几位德高望重的生物医学科学家的实验室 该计划将侧重于炎症的生物学和生物化学方面的高级培训， 强调它在人类分娩中的作用。首席研究员的科学发展将由 咨询委员会的成员。赞助者是一位备受尊敬的生殖生物学家， 分子方面的长期和早产，已培训了许多临床研究员，博士后研究员，和研究生 学生临床顾问是早产临床方面的权威。每一位共同导师都是 选择的基础上广泛的专业知识，在具体方面的研究方法，以采用。 这项研究将集中在确定脂质体（LB）在花生四烯酸（AA）储存，动员和代谢中的作用。 羊膜上皮细胞内的代谢。随着妊娠期的推进，大量LB的积累是一种 羊膜细胞的显著形态特征，尽管这些结构的作用尚未明确定义。在 白细胞和其它与炎症相关的细胞，LB与酯化AA的储存有关。 此外，与AA的动员和氧化代谢相关的酶可能被招募到这些细胞中。 结构. AA是形成被认为对该过程至关重要的木兰素（PC）的专性前体 分娩。已经建立了导致PG形成的代谢途径;然而， 协调这一进程的机制仍然没有完全确定。在某种程度上，这是由于 系统：PG生物合成是一个高度动态和密切调控的过程，需要瞬时偶联 多种酶（包括磷脂酶、环加氧酶和PG合酶亚型）， 分离到不同的细胞区室。有待检验的具体假设是，羊膜细胞LB，通过 组织代谢前体（AA）和合成酶之间的功能耦合，可能是关键因素， 生产劳动所必需的PG。具体目标包括：1）确定劳动力对劳动力平衡的影响 2）确定LB与AA动员所必需的酶结合的程度， 测定代谢的影响; 3）测定LB扰动对PG产生的影响;和4）测定抑制的PG代谢的影响。 AA代谢对LB形成的影响。具体的实验将涉及互补的生物化学，分子， 免疫学和形态学评估，这将大大扩展受训者的实验室技能。 俄勒冈州立大学的LPR为医生科学家的培训提供了理想的环境，无论是在资源方面 智力支持。通过妇产科医生和基础医学之间的长期合作努力， 科学家来自各个学科，LPR作为一个独特的平台，转化研究。培训将 通过另外两个实验室的轮换来补充，每个实验室都配备了充足的资源， 除了教学性的研究生课程工作之外，还需要进行拟议的研究。

This proposal describes a rigorous five-year training program intended to facilitate the development of an independent academic career in reproductive medicine. The prinicipal investigator has completed a postdoctoral fellowship in the Laboratory of Perinatal Research (LPR) at The Ohio State University (OSU). Building upon this experience, this program has been designed to enable expansion of specific scientific skills through apprenticeship in the laboratories of several highly-regarded biomedical scientists. The program will focus on advanced training in the biological and biochemical aspects of inflammation, with specific emphasis on its role in human parturition. The principal investigator's scientific development will be mentored by members of an advisory committee. The sponsor, a well-respected reproductive biologist with expertise in the molecular aspects of term and preterm labor, has trained numerous clinical fellows, postdoctoral fellows, and graduate students. The clinical advisor is an authority on the clinical aspects of preterm labor. Each of the co-mentors was chosen based on extensive expertise in specific aspects of the research methodologies to be employed. The research will focus on defining the role of lipid bodies (LBs) in arachidonic acid (AA) storage, mobilization, and metabolism within cells of the amnion epithelium. The accumulation of numerous LBs with advancing gestation is a striking morphological feature of amniotic cells, although the role of these structures has not been clearly defined. In leukocytes and other cells associated with inflammation, LBs have been implicated in the storage of esterified AA. Furthermore, enzymes associated with the mobilization and oxidative metabolism of AA may be recruited to these structures. AA is the obligate precursor for the formation of the prostaglandins (PCs) considered critical to the process of parturition. The metabolic pathway leading to PGformation has been established; however, the physiological mechanisms that orchestrate this process remain incompletely defined. In part, this is due to the complexity of the system: PG biosynthesis is a highly dynamic and intimately regulated process, requiring the transient coupling of multiple enzymes (including phospholipases, cyclooxygenases, and PG synthase isoforms) that are otherwise segregated to different cellular compartments. The specific hypothesis to betested is that amniotic cell LBs, by organizing the functional coupling between metabolic precursor (AA) and synthetic enzymes, may factor critically into the generation of PGs necessary for labor. The specific aims include: 1) determining the influence of labor on LB accumulation; 2) establishing the degree to which LBs associate with enzymes necessary for AA mobilization and metabolism; 3) determining the effects of LB perturbation on PG production; and 4) determining the effects of inhibited AA metabolism on LBformation. Specific experiments will involve complementary biochemical, molecular, immunological, and morphological assessments, which will significantly extend the laboratory skills of the trainee. The LPR at OSU provides an ideal environment for the training of physician-scientists, both in terms of resources and intellectual support. Through long-standing collaborative efforts between obstetrician-gynecologists and basic scientists from a variety of disciplines, the LPR serves as a unique platform for translational research. Training will be supplemented through rotations in two additional laboratories, each of which is fully equipped with the resources necessary to conduct the proposed studies, in addition to didactic graduate course work.