Kisspeptin: A Novel Regulator of Insulin in Pregnancy

Kisspeptin：妊娠期胰岛素的新型调节剂

• 批准号: 10673862
• 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/10673862
• 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; 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; Placebo Control; 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.

项目概要 该提案的总体假设是 Kisspeptin 可以解释葡萄糖的许多变化 怀孕期间的新陈代谢：正常怀孕期间高水平的 Kisspeptin 会放大胰岛素释放以维持 血糖正常和相对低血糖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初始步骤是 1) 定义以下因素的影响： Kisspeptin（妊娠水平）对非孕妇胰岛素生理学的影响以及 2) 确定 Kisspeptin 是否 水平可预测 GDM 的发展。鉴于怀孕期间调节新陈代谢的因素的复杂性 和胰岛素生理学，这些初步研究旨在分离一个因素的影响：Kisspeptin。这 该提案利用金标准（高血糖和高胰岛素正常血糖钳）和生理学（混合 膳食耐受性测试）方法在随机、安慰剂对照和盲法临床试验中评估 Kisspeptin 的效果 对非孕妇胰岛素分泌和胰岛素敏感性的影响。更进一步，该赠款利用 综合样本库，包含纵向妊娠样本和患者结果数据以供测量 整个怀孕期间的 Kisspeptin 水平，并确定怀孕早期的 Kisspeptin 水平是否可以预测 GDM的发展。这笔赠款将加深我们对妊娠期高吻肽血症影响的理解 胰岛素和肠促胰岛素的生理学和 GDM 的发展。 该申请详细介绍了一个为期五年的综合培训计划，用于指导患者的职业发展 定向研究。申请人提出专门构建的研究，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。为了实现这一目标 为了实现这一目标，她选择了具有互补专业知识的导师：Stephanie Seminara 博士是 Kisspeptin 领域的专家 生理学，在人体生理学研究方面具有深厚的背景，她是生殖中心的主任 马萨诸塞州综合医院 (MGH) 内分泌科；帕特里克·卡塔拉诺博士是怀孕方面的专家 生理学和妊娠糖尿病，塔夫茨大学妇产科教授 医学院、母婴研究所首席研究员； Jose Florez 博士是一位专家 他研究糖尿病发展的生理机制，是麻省总医院糖尿病科的主任。这 指导团队将为申请人提供良好的定位，使其能够在以下领域开展成功的独立调查职业生涯： 新陈代谢，重点关注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作业和研讨会、实践 实践经验以及具有不同科学专业知识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独立、学术的基础 作为一名医师科学家，拥有人类代谢疾病转化研究的专业知识。