Elucidating Determinants of Gestational Beta-Cell Adaptation and Failure

阐明基因工程β细胞适应和失败的决定因素 候选人是医学博士。接受过临床内分泌学培训， 指导研究和职业发展计划在遗传学，生理学， 马萨诸塞州总医院（MGH）妊娠期葡萄糖代谢的内分泌学。 候选人将在杰出的导师的指导下完成拟议的计划 具有互补专业领域的研究人员：1）Jose C. Florez，总检察长 糖尿病科和世界公认的2型糖尿病转化研究的领导者 Ravi Thadhani博士，MGH肾脏科主任， 妊娠期医学疾病的转化研究。候选人将承诺 课程，接受指导，并获得生理调查的实践经验， 纵向和遗传数据分析，分析人类血浆的先进技术，以及安全， 在产科人群中进行合乎道德的研究。该计划将独特地装备 候选人的技能，成为一个独立的医生，科学家调查 妊娠期内分泌和代谢疾病。在怀孕期间， 葡萄糖代谢的变化。到妊娠晚期，母体胰腺β细胞必须 在面对明显的妊娠诱导胰岛素时， 阻力在5-10%的孕妇中，这种β细胞适应失败，导致妊娠 糖尿病（GDM）。GDM与昂贵的不良围产期结局和高风险相关。 未来母亲患2型糖尿病的风险目前还不清楚GDM在多大程度上是由母体 怀孕前的β细胞缺陷或循环激素失衡， 在怀孕期间刺激β细胞。拟议研究的科学目标是评估 母体遗传和循环妊娠激素对β细胞 怀孕的适应和失败。在目标1中，候选人将决定初选 母体遗传变异改变GDM风险的生理机制。在目标2中， 候选人将测试孕妇的血浆是否含有内源性β细胞 GDM中缺乏的刺激活性。为了实现这些目标，候选人将 在两个队列中研究孕妇：一个建立，具有横截面生理数据 另一个正在积极注册，具有纵向生理数据。这项研究可能会定义 导致妊娠期高血糖症的关键途径，可以在新的妊娠中靶向- GDM的具体预防和治疗策略。

Elucidating Determinants of Gestational Beta-Cell Adaptation and Failure The candidate is an M.D. trained in clinical endocrinology who will undertake a five-year mentored research and career development program in the genetics, physiology, and endocrinology of glucose metabolism in pregnancy at Massachusetts General Hospital (MGH). The candidate will complete the proposed program under the mentorship of prominent researchers with complementary areas of expertise: 1) Dr. Jose C. Florez, Chief of the MGH Diabetes Unit and world-recognized leader in translational investigation of type 2 diabetes genetics and 2) Dr. Ravi Thadhani, Chief of the MGH Nephrology Division and expert in translational investigation of medical disorders in pregnancy. The candidate will undertake coursework, receive mentorship, and gain practical experience in physiologic investigation, longitudinal and genetic data analysis, advanced techniques to profile human plasma, and safe, ethical conduct of research in the obstetric population. This program will uniquely equip the candidate with the skills necessary to become an independent physician-scientist investigating endocrine and metabolic disease in pregnancy. Indeed, during pregnancy, there are profound changes in glucose metabolism. By late gestation, maternal pancreatic beta cells must dramatically increase insulin secretion in the face of marked pregnancy-induced insulin resistance. In 5-10% of pregnant women, this beta-cell adaptation fails, resulting in gestational diabetes mellitus (GDM). GDM is associated with costly adverse perinatal outcomes and a high risk of future maternal type 2 diabetes. It is unclear to what extent GDM results from maternal beta-cell defects that preceded pregnancy or from an imbalance of circulating hormones that stimulate the beta cell during gestation. The scientific goal of the proposed research is to assess the contribution of maternal genetics and circulating gestational hormones to beta-cell adaptation and failure in pregnancy. In Aim 1, the candidate will determine the primary physiologic mechanism(s) by which maternal genetic variants alter the risk of GDM. In Aim 2, the candidate will test whether the plasma of pregnant women contains endogenous beta-cell stimulatory activity which is deficient in GDM. To accomplish these aims, the candidate will study pregnant women in two cohorts: one established, with cross-sectional physiologic data and one actively enrolling, with longitudinal physiologic data. The proposed research may define key pathways leading to hyperglycemia in pregnancy which can be targeted in novel pregnancy- specific prevention and treatment strategies for GDM.