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生物行为研究调查员， 肥胖，在遗传，神经和环境因素的相互作用，以影响专业化 孩子的食欲和体重她在测量儿童饮食行为方面经验丰富， 发表在遗传影响，包括FTO基因的影响。在K99/R 00中，她建议 扩展她的培训，使她能够胜任功能磁共振成像设计和分析，并使用遗传学的措施， 肥胖风险的生物行为研究。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（CANC）致力于卡内尔博士的 职业发展。她将在SLR的精神病学助理教授激活的奖项， 我会从正式导师那里获得进一步的建议，并通过非正式导师从其他 CU研究网络中的初级和高级研究人员。卡内尔博士目前持有J1签证， 转到H1-B签证，使她能够在整个K99/R 00期间在美国工作。年底前 获得该奖项后，她将获得永久居留权。 研究环境和合作者非常适合卡内尔博士的兴趣。她提议的导师 K99的负责人是艾伦·格利布特博士，他是肠道激素在饮食失调和肥胖中的作用方面的专家， 肥胖症神经影像学的著名作者她的共同导师是钟文迪博士，著名的基础 研究基因对啮齿动物和人类肥胖的影响。通过NYORC提供的设施包括 分子遗传学和激素代谢物核心实验室，负责基因分型和激素测定， 为NIH研究人员提供最低成本。卡内尔医生可以使用纽约州立精神病医院的核磁共振成像设备 研究所（NYSPI）的神经影像学，和青少年健康诊所在CNOC的招聘，医疗， 和荷尔蒙收集合作者布拉德彼得森博士（FMRI研究）和卡伦索伦博士 (CUMC青少年医学）将促进这些服务的使用。提供的培训包括以下课程： 神经影像学和遗传学（CU）;功能磁共振成像分析杂志俱乐部（CNOC/ NYSPI）;肥胖研讨会 研究（NYORC）和食欲行为（CU）;和部门特定的大轮（CNOC和SLR）。 博士Carnell在K99/R 00赠款期间的目标是作为PI提交关于额外R机制的申请 赠款，并在年底前申请R 01竞争。 K99项目的目的是研究高能量摄入增加的神经机制。 高密度（艾德）食物的肥胖青少年以及在瘦青少年谁是在高风险的肥胖，由于 母亲肥胖她将研究大脑激活的异常是否已经存在于高血压患者中。 风险青少年，表明这些因素在体重增加中的因果作用。K99受试者（受试者; Ss）将 青春期后14-18岁，22名（11名男性; 11名女性）肥胖（BMI百分位数> 95）和44名（22名男性; 22名女性）消瘦（BMI百分位数<85） 奥尔兹是从CNOC青少年门诊招募的，还有他们的母亲。在瘦的SS中， (11M; 11 F）将具有肥胖的低家族风险（LFR）（瘦的生物学母亲），22（11 M; 11 F）将具有 肥胖的高家族风险（HFR）（肥胖的生物学母亲）。学生经过简单筛选后被认为合格， 将在测试日进行初步咨询。上午8：30，Ss将消耗400 ml Boost（高 蛋白质液体膳食）以确保适度的饱腹感。上午10：30，功能性脑活动（fMRI）响应于 视觉高艾德食物线索（例如比萨饼）、低艾德食物线索（例如水果）和非食物线索（办公用品）将 使用3 T fMRI扫描仪进行评估。对高艾德食物线索的反应（相对于低艾德和非食物 提示），预计肥胖的Ss相对于瘦的Ss在前额、眶额 皮层、杏仁核、海马和纹状体（食欲奖励），背外侧激活较少 前额叶皮层（抑制食物摄入）和后下丘脑（饱腹感）。精益HFR Ss是 在食欲奖赏区，相对于瘦LFR Ss，预期显示出更大的激活， 在饱腹感/抑制食物摄入区域，反映了食物刺激的处理差异， 导致肥胖。 R 00的目的是在K99的基础上研究与遗传性肥胖相关的神经通路。 风险，这可能介导基因对食欲和体重的影响。颊部样本将从 300名14-18奥尔兹的瘦型（BMI百分位数<85），并用于对常见的肥胖相关变体进行基因分型（例如， FTO）。遗传负担评分（GBS）将通过将每个基因座的基因型乘以其每个基因座的基因型来产生。 等位基因对BMI的影响;那些在上（HGR）和下（LGR）五分位数的人将有资格。88（44名男性; 44名女性） 预计完成者：44人（22名肥胖者，22名精瘦者）肥胖遗传风险高（HGR），44人（22名 肥胖，22瘦）在低遗传风险（LGR）。程序将遵循K99，但将有一个“美联储”的条件， 其中Ss在扫描前1小时消耗400 ml Boost，并且处于“禁食”状态（400 ml水）。空腹 在体检期间将评估肠道激素水平。预计HGR中的Ghrelin高于 LGR Ss、PYY和GLP-1在LGR中升高。预计HGR将在美联储表现出更大程度的 状态下，食欲奖励区相对于LGR的激活更大，饱腹感/抑制区的激活更少。 食物摄入区域，与当前肥胖无关。

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.