Leptin and Neuroendocrine Gene Regulation in Obesity

说明(改编自应用程序) 本应用程序的长期目标是了解规则 在下丘脑中表达的编码厌食症和厌氧症的基因 多肽，以及它们与瘦素-瘦素受体轴的相互作用。这 信息将指导在大鼠身上进行的潜在药物治疗研究 肥胖，这将转化为对人类肥胖的研究和治疗。 在目标1中，瘦素受体突变的影响，Lepr-fa-f(“Koletsky”) 和Lepr-fa(“Zucker”)，对下丘脑前阿片黑素皮质素表达的影响 (POMC，编码厌食肽α-MSH的基因)，刺鼠相关 蛋白质(AGRP，一种强有力的α-MSH拮抗剂)和神经肽Y(NPY，And 在与AGRP相同的神经元中共表达的食欲肽)，将被研究 在相同的大脑解剖中使用一种非常敏感的溶液杂交 化验。Lepr-fa-f基因剂量对神经内分泌基因表达的影响 在下丘脑，身体成分和每个脂肪细胞产生的瘦素 也有待研究。假设小剂量瘦素的应用将 减少或消除内分泌、代谢和行为调整，以 减轻体重将在啮齿动物和人类身上进行多个目标的测试。 在啮齿动物实验中，瘦素将与其他已知的 厌食剂：西布曲明(一种去甲肾上腺素和5-羟色胺再摄取 抑制剂)；纳曲酮(一种已知的阿片受体拮抗剂 下丘脑POMC表达)；以及培高利特(一种多巴胺激动剂)。在人类中 实验中，小剂量瘦素将与西布曲明联合给药，或 在体重减轻10%后给药。的影响 这些治疗方法对神经内分泌基因表达、脑脊液水平的影响 将分析神经肽、能量动态平衡和身体成分。 我计划在学术医学领域从事研究工作。虽然我的背景是 分子研究相当广泛，我没有正式的经验 进行临床研究和相关统计分析。作为我的一部分 职业发展计划，我将在#年报读哥伦比亚大学的课程。 临床研究、研究设计和统计。在《目标3》和《目标4》中，我将是其中的一员 正在进行的临床研究项目，与经验丰富的 调查人员，同时追求我自己的项目方面。我的赞助商，杜兰特博士。 Leibel和Wardlaw博士在基础和临床研究方面经验丰富。他们 容易接近，对我的项目充满热情，并将促进我的 过渡到独立调查员的地位。

DESCRIPTION (adapted from the application) The long-term objectives of this application are to understand the regulation of genes expressed in the hypothalamus that encode anorectic and orexigenic peptides, and their interactions with the leptin-leptin receptor axis. This information will guide the study in rats of potential medical therapies for obesity, that will be translated to the study and treatment of human obesity. In Aim 1, the effect of the leptin receptor mutations, Lepr-fa-f ("Koletsky") and Lepr-fa ("Zucker"), on the hypothalamic expression of proopiomelanocortin (POMC, the gene which encodes the anorectic peptide alpha-MSH), agouti related protein (AGRP, a potent antagonist of alpha-MSH), and neuropeptide Y (NPY,an orexigenic peptide coexpressed in the same neurons as AGRP), will be studied within the same brain dissections using a very sensitive solution hybridization assay. The effect of gene dosage of Lepr-fa-f on neuroendocrine gene expression in the hypothalamus, body composition and leptin production per adipocyte will also be studied. The hypothesis that the administration of low dose leptin will reduce or eliminate the endocrine, metabolic and behavioral adjustments to reduced body weight will be tested in several Aims in both rodents and humans. In the rodent experiments, leptin will be co-administered with other known anorectic agents: sibutramine (a norepinephrine and serotonin reuptake inhibitor); naltrexone (an opioid receptor antagonist known to stimulate hypothalamic POMC expression); and pergolide (a dopamine agonist). In human experiments, low dose leptin will be co-administered with sibutramine, or administered after a period of 10 percent loss in body weight. The effects of these treatments on neuroendocrine gene expression, CSF levels of neuropeptides, energy homeostasis, and body composition will be analyzed. I plan an investigative career in academic medicine. Although my background in molecular research is fairly extensive, I have no formal experience in conducting clinical research and relevant statistical analysis. As part of my career development plan, I will enroll in courses at Columbia University in clinical research study design and statistics. In Aims 3 and 4, I will be part of ongoing clinical research projects, working closely with experienced investigators, while pursuing my own aspects of the projects. My sponsors, Dr. Leibel and Dr. Wardlaw, are experienced in basic and clinical research. They are easily accessible, enthusiastic about my projects, and will facilitate my transition to status as an independent investigator.