Leptin and Neuroendocrine Gene Regulation in Obesity

描述（改编自应用程序） 本应用程序的长期目标是了解法规 在下丘脑表达的基因编码厌食和食欲 肽，以及它们与瘦素-瘦素受体轴的相互作用。这 这些信息将指导大鼠的潜在医学治疗研究， 肥胖症，这将转化为人类肥胖症的研究和治疗。 在目标1中，瘦素受体突变Lepr-fa-f（“Koletsky”）的影响 和Lepr-fa（“Zucker”）对下丘脑前阿黑皮素表达的影响 (POMC，编码厌食肽α-MSH的基因）， 蛋白（AGRP，α-MSH的有效拮抗剂）和神经肽Y（NPY， 在与AGRP相同的神经元中共表达的食欲肽），将进行研究 在同一个大脑解剖中，使用非常敏感的溶液杂交， 比色法Lepr-fa-f基因剂量对神经内分泌基因表达的影响 在下丘脑中，每个脂肪细胞的身体组成和瘦素产量将 也被研究。假设低剂量瘦素的管理将 减少或消除内分泌、代谢和行为调整， 将在啮齿类动物和人类的几个目标中测试减轻体重。 在啮齿类动物实验中，瘦素将与其他已知的药物共同施用。 厌食剂：西布曲明（去甲肾上腺素和5-羟色胺再摄取 抑制剂）;纳洛酮（一种阿片受体拮抗剂， 下丘脑POMC表达）;和培高利特（多巴胺激动剂）。人 在一些实验中，低剂量瘦素将与西布曲明共同施用，或 在体重减轻10%的时期后施用。的影响 这些治疗对神经内分泌基因表达、CSF水平、 将分析神经肽、能量稳态和身体组成。 我计划在医学研究领域做一名调查员。虽然我的背景 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 根据我的职业发展计划，我将参加哥伦比亚大学的课程， 临床研究设计和统计学。在目标3和4中，我将成为 正在进行的临床研究项目，与经验丰富的 调查员，同时追求我自己的项目方面。我的赞助商，博士。 Leibel和Wardlaw博士在基础和临床研究方面经验丰富。他们 很容易接近，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.