Neurobehavioral Correlates of Familial/genetic obesity risk in adolescents

候选人的目标是成为一名独立资助的NIH生物行为研究研究员 肥胖，具有遗传、神经和环境因素相互作用的专业性 儿童的食欲和体重。她在测量儿童的饮食行为方面很有经验，并且已经 发表了关于遗传影响的文章，包括FTO基因的影响。在K99/R00中，她提议 扩展她的培训，使她能够胜任功能磁共振设计和分析，并使用基因测量 生物行为研究中的肥胖风险。纽约肥胖研究中心(NYORC)，圣卢克- 罗斯福医院(SLR)和哥伦比亚大学医学中心(CUMC)致力于卡内尔博士的 职业发展。该奖项生效后，她将成为SLR的精神病学助理教授 将从正式导师那里获得关于晋升的进一步建议，并从其他人那里获得非正式导师的指导 CU研究网络的初级和高级调查人员。卡内尔目前持有J1签证，并将 换成H1-B签证，这样她就可以在K99/R00期间在美国高效工作。到年底的时候 获奖后，她将拥有永久居留身份。 研究环境和合作者非常适合卡内尔博士的兴趣。她推荐的导师 K99的专家是Allan Geliebter博士，他是肠道激素在进食障碍和肥胖中的作用专家，以及 在肥胖的神经成像方面发表了很好的作者。她的共同导师是温迪·钟博士，她因基础知识而闻名 啮齿动物和人类肥胖的遗传影响研究。通过NYORC提供的设施包括 分子遗传和激素代谢物核心实验室，负责基因分型和激素分析 NIH调查人员的最低成本。卡内尔博士可以使用纽约州精神病院的核磁共振单元 神经成像研究所(NYSPI)和CUMC青少年健康诊所招聘、医疗、 和荷尔蒙收集。合作者布拉德·彼得森博士(CUMC功能磁共振研究)和凯伦·索伦博士 (CUMC青少年医学中心)将促进这些服务的使用。提供的培训包括以下课程 神经成像和遗传学(CU)；功能磁共振分析杂志俱乐部(CUMC/NYSPI)；肥胖研讨会 研究(NYORC)和食欲行为(CU)；以及特定部门的盛大回合(CUMC和SLR)。 卡内尔博士在K99/R00拨款期间的目标是以私人助理的身份提交关于额外R机制的申请 拨款，并在年底前竞争申请R01。 K99项目的目的是研究高能量摄入增加背后的神经机制。 肥胖青少年和肥胖高危青少年的高密度(ED)食物 母体肥胖。她将调查大脑激活的异常是否已经出现在高值 风险青少年，这表明这些因素在体重增加中起到了因果作用。K99参与者(科目；SS)将 青春期后22(11米；11英尺)肥胖(BMI百分位数为95)和44(22米；22 F)瘦(BMI百分位数和85岁) 从CUMC青少年门诊招募的老年人和他们的母亲。精益党卫军，22岁 (11岁；11岁)患肥胖症的家庭风险(LFR)较低(瘦的生母)，22名(11岁；11岁)将有肥胖的家庭风险 肥胖的高家族风险(HFR)(肥胖的生母)。经过简短筛选后被认为符合资格的SS和 最初的咨询将被邀请到测试日。上午8：30，SS将消耗400毫升Boost(高 蛋白质液体餐)，以确保适度的饱腹感。上午10：30，功能性脑活动(FMRI)对 视觉高ED食物提示(例如披萨)、低ED食物提示(例如水果)和非食物提示(办公用品)将 使用3T功能磁共振扫描仪进行评估。响应高ED食物提示(相对于低ED和非食物 提示)，肥胖SS预计在脑岛表现出比精瘦SS更大的激活，眶前叶 皮质、杏仁核、海马体和纹状体(食欲奖励)，背外侧激活较少 前额叶皮质(进食抑制)和下丘脑后部(饱腹感)。精益HFR SS是 预计与瘦肉型LFR SS相比，在胃口奖励区域表现出更大的激活，而较少的激活 在食物摄入的饱足感/抑制方面，反映了食物刺激处理的不同，这可能 会导致肥胖。 R00的目的是在K99的基础上研究与遗传性肥胖有关的神经通路 风险可以调节基因对食欲和体重的影响。口腔样本将从 300名14-18岁的瘦子(BMI百分位数和85)，并用于对常见的肥胖相关变异进行基因分型(例如， FTO)。遗传负担分数(GBS)的计算方法是将每个基因座上的基因乘以其PER值 等位基因对体重指数的影响；高(HGR)和低(LGR)五分位数的人将符合条件。88(44m；44f) 预计将有44人(22人肥胖，22人瘦)和44人(22人)处于肥胖的高遗传风险(HGR) 肥胖，22瘦)遗传风险低(LGR)。程序将遵循K99，但将有一个“联邦”条件， 其中SS在扫描前1小时摄入400毫升Boost，并处于“禁食”状态(400毫升水)。禁食 胃肠激素水平将在体检期间进行评估。预计HGR患者的Ghrelin水平高于 LGR SS、PYY和GLP-1在LGR组较高。预计HGR将在更大程度上体现在美联储 状态，在食欲奖赏区域比LGR激活更多，而在饱腹感/抑制中激活较少 食物摄取区，与目前的肥胖无关。

The candidate's goal is to become an independently funded NIH investigator in biobehavioral research on obesity, with a specialization in the interaction of genetic, neural and environmental factors to influence children's appetite and weight. She is experienced in measuring children's eating behaviour and has published on genetic influences, including effects of the FTO gene. In the K99/R00, she proposes to expand her training to become competent at fMRI design and analysis, and using measures of genetic obesity risk in biobehavioral studies. The New York Obesity Research Center (NYORC), St. Luke's- Roosevelt Hospital (SLR) and Columbia University Medical Center (CUMC) are committed to Dr. Carnell's career development. She will be Assistant Professor in Psychiatry at SLR on activation of the award, and will obtain further advice on advancement from formal mentors and via informal mentorship from other junior and senior investigators in the CU research network. Dr. Carnell currently has a J1 visa, and will move to an H1-B visa to enable her to be productive in the US for the full K99/R00 period. By the end of the award, she will have permanent residence status. The research environment and collaborators are well-suited to Dr. Carnell's interests. Her proposed Mentor for the K99 is Dr. Allan Geliebter, an expert in the role of gut hormones in eating disorders and obesity, and well-published author in neuroimaging of obesity. Her Co-mentor is Dr. Wendy Chung, well-known for basic research on genetic influences on obesity in rodents and humans. Facilities available via NYORC include Molecular Genetic and Hormone-Metabolite Core Labs, which handle genotyping and hormone assays at minimal cost for NIH investigators. Dr. Carnell can use the MRI unit at the New York State Psychiatric Institute (NYSPI) for neuroimaging, and the Adolescent Health Clinic at CUMC for recruitment, medicals, and hormone collections. Collaborators Dr. Brad Peterson (CUMC fMRI research) and Dr. Karen Soren (CUMC Adolescent Medicine) will facilitate use of these services. Training available includes courses on neuroimaging, and genetics (CU); fMRI analysis journal club (CUMC/ NYSPI); seminars on obesity research (NYORC) and appetitive behavior (CU); and department-specific grand rounds (CUMC and SLR). Dr. Carnell's goal during the K99/R00 grant is to submit applications as PI on additional R mechanism grants and by the end to apply competitively for an R01. The aim of the K99 project is to study the neural mechanisms underlying increased intake of high energy dense (ED) foods in obese adolescents as well as in lean adolescents who are at high risk of obesity due to maternal obesity. She will investigate whether abnormalities in brain activation are already present in the high risk adolescents, suggesting a causal role for these factors in weight gain. K99 participants (Subjects; Ss) will be 22 (11M;11F) obese (BMI centile>95th) and 44 (22M;22F) lean (BMI centile<85th) postpubertal 14-18 yr olds, recruited from the CUMC adolescent outpatient clinic, and their mothers. Of the lean Ss, 22 (11M;11F) will have low familial risk (LFR) for obesity (lean biological mother), and 22 (11M;11F) will have high familial risk (HFR) for obesity (obese biological mother). Ss deemed eligible after brief screening and an initial consultation will be invited to a testing day. At 8:30 am, Ss will consume 400 ml of Boost (high protein liquid meal) to ensure moderate satiety. At 10:30 am, functional brain activity (fMRI) in response to visual high ED food cues (e.g. pizza), low ED food cues (e.g. fruits), and non-food cues (office supplies) will be assessed using a 3T fMRI scanner. In response to high ED food cues (relative to low ED and non-food cues), obese Ss are expected to show greater activation relative to lean Ss in the insula, orbitofrontal cortex, amygdala, hippocampus, and striatum (appetitive reward), and less activation in the dorsolateral prefrontal cortex (inhibition of food intake) and posterior hypothalamus (satiety). Lean HFR Ss are expected to show greater activation relative to lean LFR Ss in appetitive reward areas, and less activation in satiety/inhibition of food intake areas, reflecting differences in the processing of food stimuli which may lead to obesity. The aim of the R00 is to build on the K99 to investigate neural pathways associated with genetic obesity risk which could mediate the effect of genes on appetite and weight. Buccal samples will be collected from 300 lean (BMI centile<85th) 14-18 yr olds, and used to genotype common obesity-associated variants (e.g., FTO). Genetic burden scores (GBS) will be generated by multiplying the genotype at each locus by its per allele effect on BMI; those in the upper (HGR) and lower (LGR) quintiles will be eligible. 88 (44M;44F) completers are anticipated: 44 (22 obese, 22 lean) at high genetic risk for obesity (HGR), and 44 (22 obese, 22 lean) at low genetic risk (LGR). Procedures will follow the K99 but there will be a "fed" condition, where Ss consume 400 ml Boost 1 hr before the scan, and a "fasted" condition (400 ml water). Fasting levels of gut hormones will be assessed during the physical. Ghrelin is expected to be higher in HGR than LGR Ss, and PYY and GLP-1 higher in LGR. HGR are expected to show, to a greater degree in the fed state, greater activation relative to LGR in appetitive reward areas and less activation in satiety/inhibition of food intake areas, independent of current adiposity.