Lipid Bodies and Prostaglandin Production in Labor

分娩时的脂质体和前列腺素的产生

• 批准号: 7197313
• 负责人: WILLIAM E ACKERMAN
• 金额: $ 12.53万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197313
• 关键词: Advisory Committees; Anabolism; Arachidonic Acids; Biochemical; Biochemical Reaction; Biological; Biological Models; Birth; Cell Respiration; Cells; Cellular Membrane; Cervical; Chorion; Classification; Clinical; Coupling; Cytoplasmic Organelle; Development; Dinoprostone; Discipline; Disease; Eicosanoids; Employee Strikes; Environment; Enzymes; Epithelial Cells; Epithelium; Evaluation; Fellowship; Fetal Membranes; Generations; Gynecologist; Human; In Vitro; Inflammation; Investigation; Laboratories; Leukocytes; Lipids; Mediator of activation protein; Mentors; Metabolic; Metabolic Pathway; Metabolism; Molecular; Myometrial; Ohio; Organelles; Pathway interactions; Perinatal; Personal Satisfaction; Phospholipase; Phospholipids; Physicians; Physiological; Postdoctoral Fellow; Pregnancy; Premature Labor; Principal Investigator; Process; Prostaglandin H2; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins E; Protein Isoforms; Recruitment Activity; Reproductive Medicine; Research; Research Methodology; Research Personnel; Resources; Role; Rotation; Rupture; Scientist; Site; Source; Stimulus; Structure; Students; System; Techniques; Testing; Training; Training Programs; Translational Research; Universities; Work; amnion; authority; base; biomedical scientist; career; cyclooxygenase 1; cyclooxygenase 2; design; experience; in vivo; member; programs; reproductive; research study; response; skills; synthetic enzyme

DESCRIPTION (provided by applicant): 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 PG formation 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 be tested 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 LB formation. 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.

描述（由申请人提供）：该提案描述了一个严格的五年培训计划，旨在促进生殖医学独立学术生涯的发展。首席研究员在俄亥俄州立大学围产期研究实验室（LPR）完成了博士后研究。在这一经验的基础上，该项目旨在通过在几位备受尊敬的生物医学科学家的实验室实习，扩大特定的科学技能。该计划将侧重于炎症的生物和生化方面的高级培训，特别强调其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成员指导。主办者是一位受人尊敬的生殖生物学家，在足月和早产的分子方面具有专业知识，培养了许多临床研究员，博士后研究员和研究生。临床顾问是早产临床方面的权威。每一位共同导师的选择都是基于在将要采用的研究方法的具体方面的广泛专业知识。该研究将集中于确定脂质体（LBs）在羊膜上皮细胞内花生四烯酸（AA）储存、动员和代谢中的作用。随着妊娠的推进，大量lb的积累是羊膜细胞的一个显著形态学特征，尽管这些结构的作用尚未明确定义。在白细胞和其他与炎症相关的细胞中，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结构中。AA是前列腺素（PCs）形成的专性前体，被认为对分娩过程至关重要。导致PG形成的代谢途径已经建立；然而，协调这一过程的生理机制仍未完全确定。在某种程度上，这是由于系统的复杂性：PG生物合成是一个高度动态和密切调节的过程，需要多种酶（包括磷脂酶、环加氧酶和PG合成酶同工型）的瞬间偶联，否则这些酶就会被分离到不同的细胞区室。需要验证的具体假设是，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，可能对分娩所需的PGs的产生起关键作用。具体目的包括：1)确定劳动对LB积累的影响；2)确定lb与AA动员和代谢所需酶的关联程度；3)确定LB扰动对PG产量的影响；4)测定抑制AA代谢对LB形成的影响。具体的实验将包括互补的生化、分子、免疫学和形态学评估，这将大大扩展学员的实验室技能。俄勒冈州立大学的LPR在资源和智力支持方面为培养医师科学家提供了理想的环境。通过妇产科医生和不同学科的基础科学家之间的长期合作，LPR为转化研究提供了一个独特的平台。除了教学性的研究生课程外，还将通过另外两个实验室的轮转来补充训练，每个实验室都充分配备进行拟议研究所需的资源。