INHERITED DOPAMINE LOSS

遗传性多巴胺缺失

• 批准号: 2263785
• 负责人: SUZANNE Katherine ROFFLER-TARLOV
• 金额: $ 19.1万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2263785
• 关键词: 3,4 dihydroxyphenylacetate; alleles; animal breeding; autosomal recessive trait; axon; brain disorders; cell death; cerebellum; corpus striatum; dendrites; dopamine; gamma aminobutyrate; gene expression; histology; hypothalamus; inhibitor /antagonist; laboratory mouse; linkage mapping; mazindol; mesencephalon; mutant; neurons; norepinephrine; restriction fragment length polymorphism; substantia nigra; synaptosomes; tissue mosaicism; tyrosine 3 monooxygenase

This proposal outlines the continuation (years 7-12) of the study of a mutation that discriminates in its effects between the nigrostriatal and mesolimbic dopamine-containing pathways suggesting separable genetic control of these two systems that may account for their differential vulnerability to a variety of agents. The genetic mutation to be examined is weaver, an autosomal recessive mutation in mice in which the dorsal striatum suffers reduction in dopamine content and tyrosine hydroxylase activity in a pattern with strict and reproducible boundaries. The mesolimbic system escapes most but not all the effects of the gene and suffers little or no cell death. The pattern of cell death seen in weaver is remarkably similar to that seen in Parkinson's disease and in humans and animals made parkinsonian through exposure to the neurotoxin MPTP. Evidence gathered in the last grant period point to defects in axonal and dendritic processes as being close to the primary cellular action of the mutant gene. Although cell death in the midbrain is restricted to subpopulations, "spared" groups of cells are not wholly invulnerable for they show pathology as measured by deficits in high affinity uptake of 3H dopamine in target regions. Experiments are planned to examine the hypothesis that differentiated properties of neuronal processes are targets of weaver and that a single dose of the gene will affect uptake without causing cell death. Experiments are also planned to explore the possibility that the gene affects many more neurons than it kills. Gradients in the distribution of dopamine uptake sites in the striatum will be mapped and examined for convergence with the pattern of dopamine loss. Such a gradient may underlie the pattern of cell populations vulnerable to cell death in weaver and in parkinsonian disorders and may be a key to understanding a number of diseases of the basal ganglia including Huntington's disease and parkinsonism. A main aim of the new grant period will be to identify intrinsic and extrinsic effects of the weaver gene in the nigrostriatal system. Chimeric mice of normal and weaver parentage will be used to provide an unambiguous answer as to whether the dopamine-containing cells are a primary cellular target of the gene. 3H thymidine birthdating and studies of fluorogold accumulation will be employed to determine the fate of striatal island cells. The search for the gene has been initiated and will be continued using genetic linkage studies.

该提议概述了一项研究的延续（7 - 12年） 突变会区分其在黑质纹状体和 含含有多巴胺的含有可分离遗传的途径的途径 控制这两个系统可能解释其差异的系统 对各种代理商的脆弱性。要检查的基因突变 是织布工，是背侧的小鼠常染色体隐性突变 纹状体降低了多巴胺含量和酪氨酸羟化酶 具有严格且可再现边界的模式的活动。 这 中唇系统逃脱了大多数但并非所有基因的影响 几乎没有或没有细胞死亡。 织布工中看到的细胞死亡模式 与帕金森氏病和人类和人类和 动物通过暴露于神经毒素MPTP来制作帕金森尼。 在最后一个赠款期间收集的证据，以轴突的缺陷和 树突过程与接近的主要细胞作用 突变基因。 尽管中脑的细胞死亡仅限于 亚群，“幸免”的细胞组并非完全无敌 它们显示出病理学，如3H的高亲和力摄取的缺陷所测量 目标区域中的多巴胺。 计划进行实验以检查 假设神经元过程的分化特性是目标 织布工，一个基因的一剂将影响摄取 导致细胞死亡。 还计划探索实验 该基因影响许多神经元的可能性比杀死更多的神经元。 纹状体中多巴胺摄取位点分布的梯度将 与多巴胺损失的模式进行映射并检查是否收敛。 这样的梯度可能是细胞群体模式的基础 织布工和帕金森氏症的细胞死亡，可能是 了解许多基底神经节的疾病 亨廷顿氏病和帕金森主义。 新赠款期的主要目的是确定内在的和 织布基因在黑质体系中的外在作用。 嵌合 正常和织布生的小鼠将使用明确的 关于含多巴胺的细胞是否是主要细胞的答案 基因的靶标。 3H胸苷的生育和荧光研究 积累将用于确定纹状体岛的命运 细胞。 对基因的搜索已开始，并将继续 使用遗传联系研究。