rAAV-GDNF to study mesolimbic control of body mass

rAAV-GDNF 研究中脑边缘对体重的控制

基本信息

批准号：
8094648
负责人：
RONALD J MANDEL
金额：
$ 21.98万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8094648
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 research study response trend

项目摘要

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）：我们之前发现，通过腺相关病毒（rAAV）在黑质纹状体中过度表达神经胶质细胞系源性神经营养因子（GDNF）会导致完整老年肥胖大鼠的体重显着减轻，中年大鼠，年轻大鼠体重增加不足。此外，纹状体终场中 GDNF 的过度表达对体重增加没有显着影响。迄今为止，我们已经追踪到黑质过度表达的 GDNF 对下丘脑室旁核的影响。然而，当 GDNF 在下丘脑中直接过度表达，其水平与黑质 rAAV-GDNF 达到的水平相同时，动物的体重减轻较少。这些数据可能表明黑质 GDNF 过度表达仅对下丘脑以外的细胞核产生影响。本提案旨在确定中脑边缘多巴胺（DA）从腹侧被盖区（VTA）到伏隔核（nAcc）的投射对GDNF过度表达诱导的体重减轻的贡献程度。我们的初步数据表明，在 VTA 中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，尚未观察到 GDNF 对 DA 水平或周转率的影响与 GDNF 过度表达相关，但这并不能最终排除 DA 作为 GDNF 过度表达诱导体重减轻的重要介质。目标 1 旨在确定中脑边缘 DA 投射的末端区域、nAcc 或 VTA 本身是否是 rAAV 介导的 GDNF 过度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和中脑边缘 DA 投射的共表达是否会对体重产生累加效应。目标 2 旨在确定中脑边缘 DA 在 GDNF 过度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、氧气利用率增加或表现出类似焦虑的行为，以确定 GDNF 过度表达的潜在行为影响，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脑脊液水平，以尝试全面表征 HPA 对 GDNF 过度表达的反应。公共健康相关性：该项目旨在跟进 Mandel 实验室的新发现，该发现表明，如果胶质细胞系源性神经营养因子 (GDNF) 在黑质纹状体束的多巴胺细胞中过度表达，不同年龄和不同年龄的大鼠代谢功能均减轻体重（中年肥胖大鼠）或体重不增加（年轻大鼠）。提出了一系列实验来研究哪些解剖结构有助于这种重要的新效应，并确定是否需要多巴胺来观察 GDNF 诱导的体重减轻。