Kisspeptin: A Novel Regulator of Insulin in Pregnancy

Kisspeptin：妊娠期胰岛素的新型调节剂

• 批准号: 10251024
• 负责人: Margaret Flynn Lippincott
• 金额: $ 17.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251024
• 关键词: Affect; Area; Award; Beta Cell; Biological Specimen Banks; Blinded; Cessation of life; Child; Clinical; Clinical Trials; Closure by clamp; Data; Defect; Development; Development Plans; Diabetes Mellitus; Discipline of obstetrics; Down-Regulation; Endocrine; Failure; Fasting; First Pregnancy Trimester; Foundations; General Hospitals; Genetic; Gestational Age; Gestational Diabetes; Glucose; Glucose Clamp; Glucose Intolerance; Goals; Gold; Grant; Gynecology; Health; Hormones; Human; Hyperglycemia; Hyperinsulinism; Infant; Infusion procedures; Insulin; Intervention; Investigation; KISS1 gene; Knowledge; Link; Maintenance; Massachusetts; Measures; Mentors; Metabolic; Metabolic Diseases; Metabolism; Methods; Mothers; National Institute of Child Health and Human Development; Neonatal Hypoglycemia; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Pathogenesis; Patient-Focused Outcomes; Peptides; Phase; Physicians; Physiological; Physiology; Placebos; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Principal Investigator; Production; Randomized; Reproductive Health; Research; Research Institute; Research Priority; Risk; Role; Sampling; Schedule; Scientist; Structure of beta Cell of islet; Testing; Training; Training Programs; Translational Research; United States; Universities; Woman; Writing; animal data; career; career development; design; experience; fetal; glucagon-like peptide 1; glucose metabolism; human data; human subject; impaired glucose tolerance; insulin regulation; insulin secretion; insulin sensitivity; medical schools; novel; patient oriented research; peripheral blood; pregnancy health; professor; reproductive; reproductive hormone; response; restoration

PROJECT SUMMARY The overarching hypothesis of this proposal is that kisspeptin may explain many of the changes in glucose metabolism in pregnancy: high levels of kisspeptin during normal pregnancy amplify insulin release to maintain normoglycemia, and relative hypokisspeptinemia may underlie the pathophysiologic defects in gestational diabetes mellitus (GDM). The initial steps to examining this overarching hypothesis are to 1) define the effect of kisspeptin (at pregnancy levels) on insulin physiology in non-pregnant women and 2) to determine if kisspeptin levels predict the development of GDM. Given the complexity of factors in pregnancy that regulate metabolism and insulin physiology, these initial studies are designed to isolate the effect of one factor: kisspeptin. This proposal utilizes gold standard (hyperglycemic and hyperinsulinemic euglycemic clamps) and physiologic (mixed meal tolerance test) methods in randomized, placebo-controlled and blinded clinical trials to assess kisspeptin’s impact on insulin secretion and insulin sensitivity in non-pregnant women. Going further, the grant utilizes comprehensive specimen banks with longitudinal pregnancy samples and patient outcome data to measure kisspeptin levels across pregnancy and to determine if kisspeptin levels early in pregnancy can predict the development of GDM. This grant will refine our understanding of the impact of hyperkisspeptinemia of pregnancy on insulin and incretin physiology and development of GDM. This application details a comprehensive five-year training program for mentored career development in patient- oriented research. The Applicant proposes research, including independent clinical trials, specifically constructed to provide focused training pregnancy physiology and in the mechanisms of insulin physiology. To achieve this goal, she has chosen mentors with complementary expertise: Dr. Stephanie Seminara is an expert in kisspeptin physiology with a strong background in human physiology research, and she is Chief of the Reproductive Endocrine Unit at Massachusetts General Hospital (MGH); Dr. Patrick Catalano is an expert in pregnancy physiology and gestational diabetes, and he is a Professor of Obstetrics and Gynecology at Tufts University School of Medicine and Principal Investigator in the Mother Infant Research Institute; Dr. Jose Florez is an expert in physiological mechanisms in the development of diabetes, and he is Chief of the Diabetes Unit at MGH. This mentoring team will position the Applicant well to launch a successful independent investigative career in metabolism, with a focus on pregnancy and the influence of reproductive hormones, a key NICHD research priority area. The Applicant's career development plan entails rigorous coursework and seminars, hands-on practical experience, and close guidance from scientific advisors with diverse scientific expertise. Collectively, the experience gained during this award will serve as the foundation for the Applicant's independent, academic career as a physician-scientist with expertise in translational research in human metabolic disease.

项目摘要 这个提议的首要假设是kisspeptin可以解释葡萄糖的许多变化 怀孕期间的代谢：正常怀孕期间高水平的kisspeptin会放大胰岛素的释放， 血糖正常和相对低肽血症可能是妊娠期病理生理缺陷的基础 糖尿病（GDM）。检验这一总体假设的最初步骤是：1）定义 kisspeptin（妊娠水平）对非妊娠女性胰岛素生理学的影响，以及2）确定kisspeptin 水平预测GDM的发展。考虑到怀孕期间调节新陈代谢的因素的复杂性 和胰岛素生理学，这些最初的研究旨在分离一个因素的影响：kisspeptin。这 建议使用金标准（高血糖和高胰岛素正常血糖钳夹）和生理（混合 进餐耐量试验）方法在随机、安慰剂对照和盲法临床试验中评估kisspeptin 对非妊娠妇女胰岛素分泌和胰岛素敏感性的影响。更进一步，赠款利用 全面的样本库，包含纵向妊娠样本和患者结局数据， 为了确定妊娠早期的kisspeptin水平是否可以预测妊娠早期的kisspeptin水平， GDM的发展。这项资助将使我们更好地了解妊娠高血压血症的影响 对胰岛素和肠促胰岛素生理和GDM的发展的影响。 该申请详细介绍了一项为期五年的全面培训计划，旨在指导患者的职业发展- 导向研究。申请人提出的研究，包括独立的临床试验， 提供妊娠生理学和胰岛素生理学机制的重点培训。实现这一 为了实现这一目标，她选择了具有互补专业知识的导师：斯蒂芬妮·塞米纳拉博士是接吻素方面的专家 生理学在人类生理学研究方面有很强的背景，她是生殖科科长。 马萨诸塞州总医院（MGH）内分泌科;帕特里克卡塔拉诺博士是妊娠专家 他是塔夫茨大学的妇产科教授， 医学院和母婴研究所的首席研究员;何塞·弗洛雷斯博士是一位专家 在糖尿病发展的生理机制，他是在MGH糖尿病单位主任。这 指导团队将定位申请人以及启动一个成功的独立的调查职业生涯， 代谢，重点是怀孕和生殖激素的影响，这是NICHD的一项关键研究 优先领域。申请人的职业发展计划需要严格的课程和研讨会，实践 实践经验，以及具有不同科学专长的科学顾问的密切指导。总的来说， 在此奖项期间获得的经验将作为申请人的独立，学术的基础 职业生涯作为一个物理学家，科学家在人类代谢疾病的转化研究的专业知识。