rAAV-GDNF to study mesolimbic control of body mass

rAAV-GDNF 研究中脑边缘对体重的控制

• 批准号: 8255585
• 负责人: RONALD J MANDEL
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255585
• 关键词: Accounting; Adrenal Glands; Adult; Adverse effects; Age; Alcoholism; Animals; Anxiety; Behavior; Behavioral; Biological; Body Weight; Body Weight decreased; Brain; Caring; Cause of Death; Cell Nucleus; Cells; Cigarette; Clinical Trials; Corpus striatum structure; Data; Dopamine; Energy Intake; Epidemic; Figs - dietary; Genetic; Health; Hormones; Hypothalamic structure; Injection of therapeutic agent; Intervention; Intraventricular Injections; Laboratories; Leptin; Life Style; Measures; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolism; Morbidity - disease rate; Motor Activity; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleus Accumbens; Obesity; Operative Surgical Procedures; Overweight; Oxygen; Parkinson Disease; Pituitary Gland; Play; Poverty; Rattus; Recombinant adeno-associated virus (rAAV); Recombinants; Research; Resistance; Risk; Role; Series; Serum; Signaling Molecule; Site; Smoking; Structure; Ventral Tegmental Area; Weight; Weight Gain; adeno-associated viral vector; aged; base; design; gene therapy; glial cell-line derived neurotrophic factor; hypothalamic-pituitary-adrenal axis; innovation; middle age; novel; obesity treatment; paraventricular nucleus; population based; public health relevance; research study; response; trend

DESCRIPTION (provided by applicant): We have previously discovered that over-expression of glial cell line-derived neurotrophic factor (GDNF) via adeno-associated virus (rAAV) in the nigrostriatal tract in leads to highly significant weight loss in intact aged obese rats, middle aged rats, and lack of weight gain in young rats. Moreover, GDNF over-expression in striatal terminal fields has no significant effect on weight gain. To date, we have traced the effect of nigral over-expressed GDNF to the paraventricular nucleus of the hypothalamus. However, when GDNF is over-expressed directly in hypothalamus at levels equal to those achieved with nigral rAAV-GDNF, the animals lose less weight. These data may suggest that nigral GDNF over-expression is having effects in nuclei outside just the hypothalamus. The present proposal is designed to determine the extent to which the mesolimbic dopamine (DA) projection from the ventral tegmental area (VTA) to the nucleus accumbens (nAcc) contributes to GDNF-over-expression induced weight loss. We have preliminary data indicating that injections of recombinant adeno-associated viral vector (rAAV)-GDNF in VTA also leads to weight loss in rats. Thus, far, no effect of GDNF on DA levels or turnover has been related to GDNF over-expression has been observed but this does not conclusively rule out DA as an important mediator of GDNF over-expression induced weight loss. Aim 1 is designed to determine if the terminal field of the mesolimbic DA projection, the nAcc or the VTA itself is the site of action of rAAV-mediated GDNF over-expression induced weight loss. Secondarily, we will determine if co-expression in the nigrostriatal tract and the mesolimbic DA projection produces an additive effect on body weight. Aim 2 is designed to determine the extent to which mesolimbic DA plays a direct role in GDNF-over-expression induced weight loss. We will take care to determine if our animals are hyperactive, have increased oxygen utilization, or display anxiety-like behaviors to determine potential behavioral effects of GDNF over-expression that may account for the observed weight loss. We will also measure serum and CSF levels of hypothalamic-pituitary-adrenal (HPA) axis hormones and downstream signaling molecules to try to fully characterize the HPA response to GDNF over-expression. PUBLIC HEALTH RELEVANCE: This project is aimed at following up on the novel discovery from the Mandel laboratory showing that if glial cell line-derived neurotrophic factor (GDNF) is over-expressed in the dopamine cells of the nigrostriatal tract, rats of varying ages and metabolic function all lose weight (middle aged- aged obese rats) or fail to gain weight (younger rats). A series of experiments are proposed to look at which anatomical structures contribute to this important novel effect and to determine if dopamine is required to observe GDNF-induced weight loss.

描述（由申请人提供）：我们先前已经发现，通过腺相关病毒（rAAV）在黑质纹状体束中过度表达胶质细胞系衍生的神经营养因子（GDNF）导致完整的老年肥胖大鼠、中年大鼠高度显著的体重减轻，而年轻大鼠体重增加不足。此外，GDNF在纹状体终末野的过表达对体重增加没有显著影响。到目前为止，我们已经追踪了黑质过表达GDNF对下丘脑室旁核的影响。然而，当GDNF直接在下丘脑中过表达时，其水平等于用黑质rAAV-GDNF实现的水平，动物体重减轻较少。这些数据可能表明，黑质GDNF过度表达仅在下丘脑以外的核团中产生影响。本建议旨在确定中脑边缘多巴胺（DA）从腹侧被盖区（VTA）投射到延髓核（nAcc）有助于GDNF过度表达诱导的体重减轻的程度。我们有初步的数据表明，在腹侧被盖区注射重组腺相关病毒载体（rAAV）-GDNF也会导致大鼠体重减轻。因此，到目前为止，没有观察到GDNF对DA水平或周转的影响与GDNF过表达有关，但这并不能最终排除DA作为GDNF过表达诱导的体重减轻的重要介质。目的1旨在确定中脑边缘DA投射的终末区域、nAcc或VTA本身是否是rAAV介导的GDNF过表达诱导的体重减轻的作用位点。其次，我们将确定黑质纹状体束和中脑边缘DA投射的共表达是否对体重产生累加效应。目的2旨在确定中脑边缘DA在GDNF过表达诱导的体重减轻中发挥直接作用的程度。我们将注意确定我们的动物是否过度活跃，是否增加了氧气利用，或是否表现出焦虑样行为，以确定GDNF过度表达的潜在行为效应，这可能是观察到的体重减轻的原因。我们还将测量下丘脑-垂体-肾上腺（HPA）轴激素和下游信号分子的血清和CSF水平，以充分表征HPA对GDNF过表达的反应。 公共卫生关系：该项目旨在跟进来自Mandel实验室的新发现，该发现表明，如果胶质细胞系衍生的神经营养因子（GDNF）在黑质纹状体束的多巴胺细胞中过度表达，则不同年龄和代谢功能的大鼠都减轻体重（中年肥胖大鼠）或无法增加体重（年轻大鼠）。提出了一系列的实验来观察哪些解剖结构有助于这种重要的新效果，并确定是否需要多巴胺来观察GDNF诱导的体重减轻。