BLOOD/BRAIN BARRIER AND LEPTIN TRANSPORT IN OBESITY

肥胖症中的血/脑屏障和瘦素转运

• 批准号: 6476258
• 负责人: ABBA J KASTIN
• 金额: $ 32.83万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476258
• 关键词: adrenalectomy; albumins; blood brain barrier; circadian rhythms; cytokine receptors; disease /disorder model; experimental brain lesion; fasting; genetically modified animals; high performance liquid chromatography; immunocytochemistry; laboratory mouse; laboratory rat; leptin; membrane transport proteins; monoclonal antibody; nutrition related tag; obesity; perfusion; pharmacokinetics; protein localization; protein purification; protein transport; receptor mediated endocytosis; vascular endothelium

DESCRIPTION: (Applicant's abstract) Leptin, a peripherally produced polypeptide, causes weight loss after crossing the blood-brain barrier (BBB) to enter the brain where it is considered to exert a major regulatory function in obesity. Paradoxically, in obesity blood levels of leptin are increased, resulting in what has been called "leptin resistance," accompanied by relatively low levels of leptin in the cerebrospinal fluid (CSF). It has been proposed that the mechanism causing this "resistance" is decreased passage of leptin across the BBB by the transport system we have described in non-obese animals. Here, we shall use well-established techniques to determine the pharmacokinetics of the transport of leptin across the BBB in rodents with dietary, genetic, and lesioned obesity. Quantification will involve multiple-time regression analysis and perfusion. HPLC will ensure that the material entering the brain is intact and capillary depletion, with washout, will ensure that leptin does not remain bound to the endothelium. Albumin will be co-injected to correct for leakage and non- specific passage. Saturability, the self-inhibition of transport, will be determined with unlabeled leptin. Autoradiography with quantitative image analysis will determine in obese animals the sites of localization of the leptin transporters, which will be isolated and identified, and their activity (energy and ion dependence) determined in cerebral endothelia cells. Preliminary results already support our hypothesis that the transport of leptin across the BBB is decreased in some forms of obesity. Although this defect might not explain all forms of "leptin resistance" in obesity, the transport system for leptin across the BBB does provide an appropriate target of regulatory control that is susceptible to experimental and eventual therapeutic manipulation.

描述：（申请人的摘要）瘦素，一种外围产生的 多肽在越过血脑屏障后导致体重减轻 （BBB）进入被认为施加专业的大脑 肥胖症的调节功能。矛盾的是，肥胖血液水平 瘦素的增加，导致所谓的“瘦素 抗性，“伴随着相对较低的瘦素 脑脊液（CSF）。已经提出了机制 引起这种“耐药性”是瘦素通过BBB的降低 通过运输系统，我们在非肥胖动物中描述了。这里， 我们将使用良好的技术来确定 瘦素跨BBB啮齿类动物运输的药代动力学 饮食，遗传和病变的肥胖症。量化将涉及 多次回归分析和灌注。 HPLC将确保 进入大脑的材料是完整的，毛细血管耗尽，有 冲洗，将确保瘦素不会与 内皮。白蛋白将被共同注射以纠正泄漏和非 - 具体段落。饱和性，自身抑制运输，将 用未标记的瘦素确定。自显影和定量 图像分析将在肥胖动物中确定定位部位 瘦素转运蛋白，将被隔离和识别，并且 它们在脑中确定的活性（能量和离子依赖性） 内皮细胞。初步结果已经支持我们的假设 瘦素跨BBB的运输以某些形式减少 肥胖。尽管这种缺陷可能无法解释所有形式的“瘦素 在肥胖症中的耐药性，即leptin跨BBB的运输系统 确实提供了适当的监管控制目标 容易受到实验和最终的治疗操作。