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

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、复发性疾病，29% 的美国人一生中都受到其困扰1,2, 会致残2并增加死亡率3。 AUD 需要新的药物靶点和神经生物学见解。该行政补充以初步数据为指导，旨在扩大对基因变异的研究磷酸二酯酶 10A (PDE10A) 在英国生物银行进行（以及相关的磷酸二酯酶、腺苷酸酶）调节酒精相关 cAMP 级联的环化酶和蛋白激酶 A 相关蛋白）种族和社会经济多样化的我们所有人数据集。特别地，目标 1 将使用两个基因分型阵列和全基因组序列数据集，以识别与问题相关的 PDE10A 基因变异酒精使用，由 AUDIT-C 评分和酒精使用相关诊断定义，及其表达以及与常见的精神疾病和肥胖相关诊断的遗传相关性。本次行政补充品将增加家长资助的影响，以识别 PDE10A 和其他基因中的新基因变异 cAMP 级联调节基因重新利用新型可翻译 PDE 抑制剂来治疗 AUD。这补充品将提高基因发现的敏感性和普遍性，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“All of Us”数据集迫在眉睫鉴于已知的不公平的健康社会决定因素与遗传因素相互作用，在酒精中的作用美国境内的相关发病率和合并症。