Oprk1-regulated neurocircuitry and phenotypes of alcohol use disorder
Oprk1 调节的神经回路和酒精使用障碍的表型
基本信息
- 批准号:10753867
- 负责人:
- 金额:$ 56.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-02 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AbstinenceAcuteAffectAffectiveAlcohol PhenotypeAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholsAmygdaloid structureAnimal ModelAnxietyBehaviorBehavioralCRISPR/Cas technologyCell NucleusCharacteristicsChronicCognitiveComplementCre lox recombination systemDataDependenceDevelopmentDiseaseDissectionDopamineDynorphinsExcisionFoundationsGene ExpressionGenesGeneticGoalsHealthHeavy DrinkingHumanImpaired cognitionInfusion proceduresKnowledgeLiteratureMedialMediatingMemory impairmentMental DepressionMidbrain structureMotivationNational Institute on Alcohol Abuse and AlcoholismNeuronsNucleus AccumbensOutcomePathogenicityPatternPhenotypePrefrontal CortexPrincipal InvestigatorPublic HealthPublishingRat TransgeneRattusReceptor GeneRecoveryRegulationRelapseResearchRoleSelf AdministrationSelf MedicationShort-Term MemoryStrategic PlanningSystemTestingTherapeuticVentral Tegmental AreaViralWithdrawalWorkalcohol abuse therapyalcohol comorbidityalcohol exposurealcohol measurementalcohol relapsealcohol use disorderbehavioral phenotypingchronic alcohol ingestioncognitive controlcompliance behaviordesigndopaminergic neuroneffective therapyexecutive functiongenetic approachgenetic manipulationinterdisciplinary approachkappa opioid receptorsknock-downmRNA Expressionmaladaptive behaviornegative affectneural circuitneuroadaptationnovel strategiesnovel therapeutic interventionoverexpressionpersonalized medicinepersonalized therapeuticreduce symptomsresponsesuccesstherapeutic targettherapeutically effectivetherapy designtherapy developmenttreatment adherencetreatment strategyvirus geneticswelfare
项目摘要
Project Summary. A fundamental characteristic of alcohol use disorders is the loss of control over
alcohol consumption that results in progressively escalating levels of alcohol use and facilitates the
progression to alcohol-dependence. Given the comorbidity of alcohol dependence and disorders of affect
such as depression is extremely high, it has been posited that self-medication of negative affective states
contributes to continued excessive alcohol use and relapse. Furthermore, negative affective states
produced by chronic alcohol exposure can influence the neurocircuitry of cognitive control systems to
perpetuate further excessive alcohol use. Once that degree of dysregulation is reached, components of
the dependence cycle serve to facilitate each other in a manner that is extremely deleterious to personal,
familial and societal welfare. The principal investigator’s long-term goal is to identify effective
therapeutic targets and strategies for the treatment of alcohol use disorder (AUD). The objective of this
application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in Oprk1
(kappa-opioid receptor gene)-regulated systems that occur in response to chronic alcohol exposure and
contribute to maladaptive behavioral regulation. The central hypothesis is that the Oprk1-regulated
neurocircuitry becomes progressively dysregulated in a manner that promotes the continued excessive
consumption of alcohol and perpetuates the cycle of alcohol dependence. The rationale for the proposed
studies is that understanding the contribution of dysregulated Oprk1 expression in AUD will lay the
foundation for the development of effective therapies designed to alleviate maladaptive behavioral
regulation produced by alcohol dependence. This hypothesis will be tested by utilizing inducible and
conditional CRISPR/CAS9 gene editing and chemogenetic approaches to recapitulate or ameliorate
symptoms of alcohol dependence in non-selected and transgenic rats. Animal models of operant alcohol
self-administration, negative affective-like behavior and executive function including working memory
will serve as functional end-points to systematically investigate the role of Oprk1 expression in
maladaptive behavioral regulation related to alcohol dependence. In addition, Oprk1 gene expression will
be assessed as a complement to the behavioral approaches. The proposed research will help to identify
the functional importance of neuroadaptations in Oprk1-regulated systems that result from chronic
alcohol exposure and will provide much needed information regarding the influence of Oprk1 on the
neurocircuitry of AUD-related phenotypes. Such a contribution is significant because it will help identify
and develop therapeutic targets to treat AUD that focus on the removal of maladaptive phenotypes; a
strategy that should greatly increase treatment compliance and decrease rates of relapse.
项目摘要。酒精使用障碍的一个基本特征是失去对酒精的控制。
酒精消费导致酒精使用水平逐步上升,并促进
发展成酒精依赖。考虑到酒精依赖和情感障碍的合并症
例如抑郁症的发病率非常高,因此人们认为,
导致持续过量饮酒和复发。此外,消极的情感状态
慢性酒精暴露所产生的神经递质会影响认知控制系统的神经回路,
继续过量饮酒。一旦达到这种程度的失调,
依赖循环以一种对个人极其有害的方式相互促进,
家庭和社会福利。主要研究者的长期目标是确定有效的
治疗酒精使用障碍(AUD)的治疗目标和策略。的目的
应用,这是追求这一目标的下一步,是了解Oprk 1中的神经适应
(κ-阿片受体基因)调节系统,发生在响应慢性酒精暴露和
导致行为调节失调核心假设是Oprk 1调节的
神经回路以一种促进持续过度的
饮酒并使酒精依赖的循环永久化。建议的理由
了解Oprk 1表达失调在AUD中的作用将为研究提供基础。
旨在缓解适应不良行为的有效疗法开发基金会
由酒精依赖产生的调节。这一假设将通过利用诱导和
有条件的CRISPR/CAS9基因编辑和化学遗传学方法来重现或改善
酒精依赖的症状在非选择和转基因大鼠。操作性酒精的动物模型
自我管理、负性类情感行为和包括工作记忆在内的执行功能
将作为功能性终点,系统研究Oprk 1表达在
与酒精依赖相关的适应不良行为调节。此外,Oprk 1基因表达将
作为行为方法的补充进行评估。拟议的研究将有助于确定
神经适应在Oprk 1调节系统中的功能重要性,
酒精暴露,并将提供有关Oprk 1对
AUD相关表型的神经回路。这种贡献是重要的,因为它将有助于确定
并开发治疗AUD的治疗靶点,重点是消除适应不良的表型;
这将大大提高治疗依从性并降低复发率。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Brendan M Walker其他文献
Brendan M Walker的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Brendan M Walker', 18)}}的其他基金
The Role of Kappa-Opioid Receptors in Alcohol Use Disorders
Kappa-阿片受体在酒精使用障碍中的作用
- 批准号:
9986995 - 财政年份:2019
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Kappa-Opioid Receptors in Alcohol Use Disorders
Kappa-阿片受体在酒精使用障碍中的作用
- 批准号:
10473825 - 财政年份:2019
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Kappa-Opioid Receptors in Alcohol Use Disorders
Kappa-阿片受体在酒精使用障碍中的作用
- 批准号:
10241455 - 财政年份:2019
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence
强啡肽/κ-阿片类药物系统在酒精依赖中的作用
- 批准号:
8240413 - 财政年份:2011
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence
强啡肽/κ-阿片类药物系统在酒精依赖中的作用
- 批准号:
8442394 - 财政年份:2011
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence
强啡肽/κ-阿片类药物系统在酒精依赖中的作用
- 批准号:
8085608 - 财政年份:2011
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence
强啡肽/κ-阿片类药物系统在酒精依赖中的作用
- 批准号:
8828026 - 财政年份:2011
- 资助金额:
$ 56.44万 - 项目类别:
The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence
强啡肽/κ-阿片类药物系统在酒精依赖中的作用
- 批准号:
9243184 - 财政年份:2011
- 资助金额:
$ 56.44万 - 项目类别:
Chronic Ethanol Consumption, Opioids and Dopamine
慢性乙醇消耗、阿片类药物和多巴胺
- 批准号:
7168858 - 财政年份:2004
- 资助金额:
$ 56.44万 - 项目类别:
Chronic Ethanol Consumption, Opioids and Dopamine
慢性乙醇消耗、阿片类药物和多巴胺
- 批准号:
6738605 - 财政年份:2004
- 资助金额:
$ 56.44万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 56.44万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 56.44万 - 项目类别:
Operating Grants