CHARACTERIZATION OF GDNF ALPHA 1 (GFR ALPHA 1) RECEPTOR

GDNF ALPHA 1 (GFR ALPHA 1) 受体的特征

基本信息

项目摘要

Glial cell line-derived neurotrophic factor (GDNF) rescues motoneurons and nigral dopaminergic (DA) cells from induced cell death in different species of animals. In addition, GDNF results in a remarkable improvement of behavioral functions in Parkinsonian monkeys. A high affinity receptor for GDNF has been cloned (GFR alpha 1), whose pattern of expression indicates that it is not restricted to those brain areas containing motoneurons and DAergic cells, suggesting that GDNF might activate several sub-types of cells. To identify the phenotype of GFR alpha 1 expressing cells, we used a combination of anatomical techniques and found that GFR alpha 1 is expressed in defined populations of cells. As expected, we found that GFR alpha 1 is expressed in DAergic cells of the substantia nigra compacta (SNC) and the ventral tegmental area. In addition, GFR alpha 1 is expressed in GABAergic cells located either in the lateral SNC or in the substantia nigra reticulata (SNR). These GABAergic cells are more abundant in the caudal levels of the SNR. Our results suggest that GDNF-induced improvements in the behavior of hemi-parkinsonian animal models might be also mediated by GDNF actions on GABAergic cells in the SNR. We will use a hemi-parkisonian rat and a mouse model to test this hypothesis. Within the hippocampal formation, GFR alpha 1 expressing cells are either glutaminergic (subicular, pyramidal and granule cells) or GABAergic (interneurons). The glutaminergic subicular neurons constitute a major excitatory input to the nucleus accumbens(NAcc), suggesting that actions of GDNF on subicular GFR alpha 1 expressing cells might result in regulation of cells located in the Nacc. We propose to investigate the nature of these cells. We found that hippocampal GABAergic cells expressing GFR alpha 1 contain the Ca2+-binding protein parvalbumin (PV). Furthermore, most of the hippocampal neurons that contain PV express GFR alpha 1. As PV interneurons are the main source of nerve growth factor (NGF) in the hippocampus (71% of NGF positive cells contain PV), we will investigate to what extent GDNF, via its GFR alpha 1 might regulate the expression of NGF in PV containing cells. Published results show that either GDNF- (GDNF-/-) or GFR alpha 1- (GFRa-1-/-) deficient mice lack kidneys and die one day after birth. In contrast, the brains of these mutant mice appear normal. Thus, it is believed that while GDNF and its receptor are important for the development and/or survival for the renal system, they are not essential for neurons of the CNS. Our data suggest that GFR alpha 1 is expressed in some cells that might mature after birth, therefore, we will investigate if the development and/or survival of these particular type of cells is compromised in newborn GDNF (-/-) and GFR alpha 1 (-/-) homozygous mice, and in the corresponding adult heterozygous. Using either a cerebral ischemia model (middle cerebral artery, ligation) or physical cortical injury, we found a robust up-regulation of GFR alpha 1 expression in granule cells ipsilateral to the area receiving the insult. In both models, GFR alpha 1 up-regulation peaks 6 hours following ischemia or physical injury. These results indicate that GFR alpha 1 might be part of an endogenous neuroprotective system, that is activated following a brain insult and may act as defense mechanism in the brain. We will investigate the possible brain circuitry involved in this defense mechanism and we will evaluate if a similar situation is observed during methamphetamine-induced brain injury.
胶质细胞源性神经营养因子 拯救运动神经元和黑质多巴胺能(DA)细胞 在不同物种的动物中诱导细胞死亡。此外, GDNF对行为功能有显著改善 在帕金森症猴子身上。GDNF的高亲和力受体 被克隆(GFRα1),其表达模式表明 它并不局限于那些含有运动神经元的大脑区域 和DAR能细胞,表明GDNF可能激活了几个 单元格的子类型。鉴定GFRα1的表型 为了表达细胞,我们使用了解剖学技术的组合 并发现GFRα1在特定的人群中表达 细胞。不出所料,我们发现GFRα1在 黑质致密质(SNC)的DAR能细胞 腹侧被盖区。此外,GFRα1表达为 GABA能细胞位于外侧黑质或黑质 黑质(SNR)。这些GABA能细胞 在SNR的尾部水平丰富。我们的结果表明 胶质细胞源性神经营养因子对偏侧帕金森患者行为的改善 动物模型也可能通过GDNF的作用而介导 SNR中的GABA能细胞。我们将用一只半帕基斯尼亚大鼠 并用一只老鼠模型来验证这一假设。在海马区 形成,表达GFRα1的细胞要么是谷氨酸能的 (下丘、锥体和颗粒细胞)或GABA能 (中间神经元)。谷氨酰胺能下神经元构成 伏核(NAcc)的主要兴奋性输入,提示 胶质细胞源性神经营养因子对肾小管上皮细胞GFRα1表达的影响 可能导致对位于NACC中的细胞的调节。我们建议 来研究这些细胞的性质。我们发现海马体 表达GFRα1的GABA能细胞含有钙结合 蛋白质小白蛋白(PV)。此外,大部分海马区 含有PV的神经元表达GFRα1。作为PV中间神经元 是人体内神经生长因子(NGF)的主要来源 海马区(71%的NGF阳性细胞含有PV),我们将 研究GDNF通过其GFRα1可能达到的程度 调节含PV细胞中NGF的表达。已出版 结果表明,无论是GDNF-(GDNF-/-)还是GFRα1- (GFRa-1-/-)缺陷小鼠缺乏肾脏,出生后一天死亡。 相比之下,这些突变小鼠的大脑看起来是正常的。因此,它 人们认为,虽然GDNF及其受体对 肾系统的发育和/或生存,它们不是 对中枢神经系统的神经元来说是必不可少的。我们的数据表明,GFRα 1在一些可能在出生后成熟的细胞中表达,因此, 我们将调查这些生物的发展和/或生存 特定类型的细胞在新生儿GDNF(-/-)中受损 GFRα1(-/-)纯合子小鼠,以及相应的成人 杂合子。使用脑缺血模型(中间 大脑动脉结扎)或物理皮质损伤时,我们发现 颗粒细胞中GFRα1表达的强势上调 在接受侮辱的区域的同一侧。在这两种模型中,GFR 脑缺血或体力活动后6小时α1上调达峰值 受伤。这些结果表明,GFRα1可能是一种 内源性神经保护系统,在 大脑侮辱并可能在大脑中扮演防御机制的角色。我们会 调查这一防御过程中可能涉及的大脑回路 机制,我们将评估是否观察到类似的情况 在甲基苯丙胺引起的脑损伤期间。

项目成果

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BARRY J. HOFFER其他文献

BARRY J. HOFFER的其他文献

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{{ truncateString('BARRY J. HOFFER', 18)}}的其他基金

PHARMACOLOGICAL CORRELATES OF AGING IN BRAIN CELL GRAFTS
脑细胞移植物衰老的药理学相关性
  • 批准号:
    6311452
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
PHARMACOLOGICAL CORRELATES OF AGING IN BRAIN CELL GRAFTS
脑细胞移植物衰老的药理学相关性
  • 批准号:
    6097978
  • 财政年份:
    1999
  • 资助金额:
    --
  • 项目类别:
PHARMACOLOGICAL CORRELATES OF AGING IN BRAIN CELL GRAFTS
脑细胞移植物衰老的药理学相关性
  • 批准号:
    6267219
  • 财政年份:
    1998
  • 资助金额:
    --
  • 项目类别:
FUNCTION OF CNS NEURAL GRAFTS
中枢神经系统神经移植物的功能
  • 批准号:
    6112032
  • 财政年份:
    1998
  • 资助金额:
    --
  • 项目类别:
FETAL TISSUE TRANSPLANT AND OTHER GENE EXPRESSION SYSTEMS
胎儿组织移植和其他基因表达系统
  • 批准号:
    6111440
  • 财政年份:
    1998
  • 资助金额:
    --
  • 项目类别:
FETAL TISSUE TRANSPLANT AND OTHER GENE EXPRESSION SYSTEMS
胎儿组织移植和其他基因表达系统
  • 批准号:
    6243058
  • 财政年份:
    1997
  • 资助金额:
    --
  • 项目类别:
FUNCTION OF CNS NEURAL GRAFTS
中枢神经系统神经移植物的功能
  • 批准号:
    6243412
  • 财政年份:
    1997
  • 资助金额:
    --
  • 项目类别:
PHARMACOLOGICAL CORRELATES OF AGING IN BRAIN CELL GRAFTS
脑细胞移植物衰老的药理学相关性
  • 批准号:
    6233990
  • 财政年份:
    1997
  • 资助金额:
    --
  • 项目类别:
AMINERGIC FUNCTION IN AGING AND ALZHEIMER'S DISEASE
衰老和阿尔茨海默病中的胺能功能
  • 批准号:
    3090877
  • 财政年份:
    1992
  • 资助金额:
    --
  • 项目类别:
COMPLEX I IN PARKINSONS DISEASE
帕金森病中的复合体 I
  • 批准号:
    3415971
  • 财政年份:
    1991
  • 资助金额:
    --
  • 项目类别:

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一种小的钙结合蛋白可能是稳定感觉毛细胞静纤毛伸长复合物的关键
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