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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.

摘要