THE ROLE OF DOPAMINE PATHWAY IN ALCOHOLISM

多巴胺通路在酗酒中的作用

基本信息

批准号：
6208998
负责人：
Abbas Parsian
金额：
$ 3.72万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-03-01 至 2001-02-28
项目状态：
已结题

项目摘要

The long term goal of this revised project is to define the molecular basis of the genetic contributions to the development of alcoholism. The main objective is to determine the role of enzymes and receptors involved in dopaminergic neurotransmission in the development of severe alcoholism. Optimal segregation models are consistent with an autosomal dominant mode of transmission, but only with large differences in penetrance between males and females. At the present time, it is difficult to empirically test any of the proposed models of genetic transmission for alcoholism. Whether these specific transmission models are correct or not, one practical consequence is that genetic linkage studies using such models will have little power to detect or exclude linkage. The main reason is heterogeneity in phenotypes. This is a disadvantage of the linkage approach to alcoholism or other complex psychiatric disorders. This shortcoming of linkage analysis makes the use of association studies and DNA sequence analysis of candidate genes more attractive. Genomic DNA samples from 128 alcoholic probands, 88 psychiatrically normal controls, and 317 individuals in 36 alcoholic families will be typed for restriction fragment length polymorphisms (RFLPs) with cDNA clones of enzymes of the dopamine pathway and dopamine receptors. The exons of alleles of the genes in this pathway which show positive associations with alcoholism will be sequenced to detect DNA sequence variations. Finally, RFLP associations and DNA sequence variations will be tested for cosegregation with alcoholism in pedigrees. For any sequence variation, the role of the amino acid substitutions in altering enzymatic activity or receptor functioning will be clarified. These results may provide evidence for the role of any of the enzymes or receptors in the dopamine pathway in the development of alcoholism. The sequencing of intronic DNA near any disease associated sequence difference should allow the development of PCR based polymorphisms which can distinguish individuals carrying the mutant and normal genes. These would be useful in population studies to identify individuals at risk for developing alcoholism.

该修订项目的长期目标是定义分子对酒精中毒发展的遗传贡献的基础。这主要目的是确定涉及的酶和受体的作用在多巴胺能神经传递中，在严重酒精中毒的发展中。最佳分离模型与常染色体显性模式一致传输的，但只有很大的差异男性和女性。目前，很难从经验上测试任何提议的酒精中毒遗传传播模型。这些特定的传输模型是否正确，一个实际结果是，使用此类模型的遗传联系研究将几乎没有能力检测或排除链接。主要原因是表型中的异质性。这是联系的缺点酒精中毒或其他复杂的精神疾病的方法。这链接分析的缺点是使用关联研究和候选基因的DNA序列分析更具吸引力。基因组DNA 来自128个酒精概率的样品，88个精神上正常对照，和36个酒精家庭中的317个人被键入限制碎片长度多态性（RFLP）与酶的cDNA克隆多巴胺途径和多巴胺受体。基因等位基因的外显子在这条途径中显示出与酒精中毒的积极关联将是测序以检测DNA序列变化。最后，RFLP协会和DNA序列变化将测试与cosegregation一起使用酗酒的谱系。对于任何序列变化，氨基的作用改变酶活性或受体功能的酸取代将被澄清。这些结果可能为任何角色提供证据多巴胺途径中的酶或受体的发展酗酒。在任何相关疾病附近的内含子DNA的测序序列差异应允许基于PCR的发展可以区分携带突变体的个体的多态性和正常基因。这些在人群研究中很有用有酗酒风险的人。