Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

背侧纹状体磷酸二酯酶 10A 和强迫性乙醇使用

基本信息

批准号：
10660892
负责人：
ERIC P ZORRILLA
金额：
$ 13.31万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660892
关键词：
Adenylate Cyclase Administrative Supplement Affective Age Alcohol abuse Alcohol consumption Alcohols American Behavioral CREB1 gene Chronic Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP DARPP Data Data Set Diagnosis Disease Dorsal Ethanol Genes Genetic Genotype Guanylate Cyclase Investigation Link Mental disorders Morbidity - disease rate Neurobiology Neurons Obesity PDE2 phosphodiesterase Pathway interactions Persons Population Protein Isoforms Proteins Relapse Role Testing United States alcohol use disorder biobank comorbidity differential expression drinking ethnic diversity genetic regulatory protein genetic variant inhibitor insight member motor behavior multidisciplinary new therapeutic target novel parent grant phosphoric diester hydrolase psychiatric comorbidity psychogenetics putamen rumination social health determinants socioeconomic diversity socioeconomics whole genome

Adenylate Cyclase Administrative Supplement Affective Age Alcohol abuse Alcohol consumption Alcohols American Behavioral CREB1 gene Chronic Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP DARPP Data Data Set Diagnosis Disease Dorsal Ethanol Genes Genetic Genotype Guanylate Cyclase Investigation Link Mental disorders Morbidity - disease rate Neurobiology Neurons Obesity PDE2 phosphodiesterase Pathway interactions Persons Population Protein Isoforms Proteins Relapse Role Testing United States alcohol use disorder biobank comorbidity differential expression drinking ethnic diversity genetic regulatory protein genetic variant inhibitor insight member motor behavior multidisciplinary new therapeutic target novel parent grant phosphoric diester hydrolase psychiatric comorbidity psychogenetics putamen rumination social health determinants socioeconomic diversity socioeconomics whole genome

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项目摘要

ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disorder that afflicts 29% of Americans in their lifetime1,2, is disabling2 and increases mortality3. New drug targets and neurobiological insight for AUD are needed. Guided by preliminary data, this administrative supplement seeks to expand studies of gene variants in phosphodiesterase 10A (PDE10A) performed in the UK Biobank (and related phosphodiesterases, adenylyl cyclases and protein kinase A-related proteins that regulate alcohol-related cAMP cascades) to studies in the ethincally and socioeconomically diverse All of Us dataset. Specially, Aim 1 will use both genotyped arrays and whole genome sequence datasets to identify PDE10A gene variants that associate with problematic alcohol use, as defined by AUDIT-C scores and alcohol use-associated diagnoses, as well as their expression and genetic correlation to often comorbid psychiatric and obesity-related diagnoses. This administrative supplement will increase the impact of the parent grant to identify novel gene variants in PDE10A and other cAMP-cascade regulating genes towards repurposing novel translatable PDE inhibitors to treat AUD. The supplement will increase the sensitivity and generalizability of genetic discovery to reflect the age, ethnic, and socioeconomic diversity of the American population. Extending our analyses to the All of Us dataset is pressing given the known role of inequitable social determinants of health, interacting with genetic factors, in alcohol- related morbidity and comorbidity within the United States.

抽象的酒精使用障碍（AUD）是一种慢性复发障碍，在其一生中遭受29％的美国人的痛苦1,2，是禁用2并增加死亡率3。需要新的药物靶标和神经生物学见解。在初步数据的指导下，这种行政补充旨在扩大对基因变异的研究磷酸二酯酶10a（PDE10A）在英国生物库（及相关磷酸二酯酶，腺苷酸调节酒精相关的营地级联反应的环酶和蛋白激酶A相关蛋白）我们所有人的数据集都在元素和社会经济上多样化。特别是，AIM 1将使用两个基因分型阵列和整个基因组序列数据集，以识别与有问题的相关性的PDE10A基因变体饮酒，由审计-C分数和与酒精相关的诊断所定义，饮酒及其表达以及与经常合并精神病和肥胖相关诊断的遗传相关性。这个行政补充剂将增加父母赠款的影响，以识别PDE10A和其他的新型基因变异营地调节基因以重新利用新型可翻译PDE抑制剂来治疗AUD。这补充将提高遗传发现的敏感性和概括性，以反映年龄，种族和美国人口的社会经济多样性。将我们的分析扩展到我们所有的数据集考虑到健康不平等的社会决定因素，与遗传因素相互作用的已知作用，在酒精中美国的相关发病率和合并症。