Lipid Bodies and Prostaglandin Production in Labor

该提案描述了一项为期五年的严格培训计划，旨在促进 生殖医学方面的独立学术生涯。首席调查员已经完成了博士后研究 俄亥俄州立大学(OSU)围产期研究实验室研究员。以此为基础 经验，这个计划的设计是为了通过学徒来扩展特定的科学技能 几位备受尊敬的生物医学科学家的实验室。 该计划将侧重于炎症的生物和生化方面的高级培训，并提供具体的 强调它在人类分娩中的作用。首席研究员的科学发展将由以下人员指导 咨询委员会的成员。赞助商是一位备受尊敬的生殖生物学家，在 足月和早产的分子方面，已经培养了许多临床研究员、博士后研究员和研究生 学生们。临床顾问是早产临床方面的权威。每个联合导师都是 根据拟采用的研究方法的具体方面的广泛专业知识进行选择。 这项研究将集中于确定脂体(Lbs)在花生四烯酸(AA)储存、动员和 羊膜上皮细胞内的代谢。随着妊娠的推进，大量磅的积累是一种 羊膜细胞具有显著的形态特征，但这些结构的作用尚未明确。在……里面 白细胞和其他与炎症相关的细胞，Lbs被认为与酯化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 结构。AA是前列腺素(PC)形成的必备前体，被认为是这一过程的关键 关于分娩的事。导致前列腺素形成的代谢途径已经建立；然而，生理上的 协调这一过程的机制仍然没有完全确定。这在一定程度上是由于 系统：PG的生物合成是一个高度动态和严密调控的过程，需要瞬间耦合 多种酶(包括磷脂酶、环氧合酶和PG合成酶亚型) 被分离到不同的细胞隔间。更好的具体假设是羊膜细胞lbs，通过 组织代谢前体(AA)和合成酶之间的功能偶联，可能是 分娩所必需的PG的产生。具体目标包括：1)确定劳动力对劳工价值的影响 积累；2)确定LBS与AA动员所必需的酶的结合程度 代谢；3)确定LB扰动对PG生产的影响；以及4)确定抑制的效果 氨基酸在脂蛋白形成上的代谢。具体的实验将涉及互补的生化，分子， 免疫学和形态学评估，这将大大扩展受训人员的实验室技能。 俄亥俄州立大学的LPR为医学科学家的培训提供了理想的环境，无论是在资源方面还是在资源方面 和智力支持。通过妇产科医生和基础医生之间的长期合作 来自不同学科的科学家，LPR是翻译研究的独特平台。培训将是 通过另外两个实验室的轮换进行补充，每个实验室都配备了充分的资源 除了讲授研究生课程的工作外，还必须进行拟议的研究。

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.