ADHD Phenotype Network: Animal Model to Clinical Trial

ADHD 表型网络：动物模型到临床试验

• 批准号: 6535963
• 负责人: FLOYD R SALLEE
• 金额: $ 23.05万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6535963
• 关键词: Tourette's syndrome; attention deficit disorder; behavior test; brain electrical activity; clinical research; comorbidity; disease /disorder etiology; dopamine; environmental exposure; gene environment interaction; gene expression; gene targeting; genetic polymorphism; genetically modified animals; human subject; human therapy evaluation; laboratory mouse; lead; neural information processing; neuropharmacology; neuropsychology; neurotransmitter antagonist; outcomes research; patient oriented research; phenotype; psychopharmacologic agent

DESCRIPTION (provided by applicant): Our network group seeks to formalize a collaboration of neuroscientists, geneticist, pharmacologists, pediatricians, and child psychiatrist so as to transcend the limitations of our present conceptualization of ADHD etiology by concentrating on non-clinical phenotypes. Non-classical phenotypes were chosen based on their shared pathophysiology involving circuitry which is amenable to "circuit-testing" of behavior and pharmacologic dissection in animal models as well as the clinic. These ADHD phenotypes involve dopaminergic (DA) pathophysiology as a core feature, and share common cortical-limbic glutamatergic neuronal (CGN) circuitry in symptom generation. Each phenotype has heuritic value to bring an understanding not only to ADHD "outliers" but for classical ADHD through the identification of shared mechanisms. One such shared mechanism we hypothesize is the glutamatergic valence of key cortical-limbic pathways (Carlsson 2000). The lead-exposed ADHD phenotype we propose as a prototype for determining the interaction of DA genotype (DRD4, DRD5, DAT) and environment producing ADHD symptoms and impairment. In our network, we have developed interposing projects at the behavioral/phenomenologic and animal model-genetic determinant levels to inform a translational "proof of concept" clinical trial. This feasibility trial will estimate effect sizes for the cortical-limbic noradrenergic (NE) releasing drug, atomoxetine. Pharmacologic dissection of ADHD phenotypes is now possible using direct DA agonists/antagonists as well as indirect agents impacting cortical-limbic glutamatergic neuronal (CGN) circuitry like atomoxetine. Major strengths of this proposal include: 1) Strong, ongoing collaborative relationships between network members; 2) novel and testable hypothesis regarding non-classical ADHD phenotypes encountered in clinical practice from which "proof of concept" pharmacologic trials can be initiated; 3) an animal model that is well characterized and highly exploitable for "circuit-testing" of antipodal behavioral features of the ADHD-TS phenotype; 4) a unique opportunity to study the neurobehavioral outcomes of an ongoing lead-exposed cohort of 212 children as the cohort reaches the time (school-age) when a clinical diagnosis of ADHD typically occurs; 5) examination of gene-environment interactions with DA-associated polymorphisms linked to ADHD phenotype expression, and 6) strong, extra-network linkages with the pediatric pharmacologic research units (PPRU) infrastructure, an animal model behavioral phenotyping laboratory, and a Howard Hughes Bioinformatics Center to expand on Arrant findings and "proof of concept' trials.

描述（由申请人提供）：我们的网络小组旨在正式化神经科学家，遗传学家，药理学家，儿科医生和儿童精神病医生的合作，以超越我们目前对ADHD病因的概念的局限性，通过专注于非临床表型。基于它们的共享病理生理学选择了非古典表型，该病理生理涉及电路，该电路可与动物模型和诊所中的行为和药理学解剖的“电路测试”。这些ADHD表型涉及多巴胺能（DA）病理生理学作为核心特征，并共享症状产生中常见的皮质 - limbic谷氨酸能神经元（CGN）电路。每种表型都具有启发性价值，不仅可以通过识别共享机制来给多动症的“异常值”带来理解的经典多动症。我们假设的一种共同的机制是关键皮质沿途径的谷氨酸能价（Carlsson 2000）。我们提出的铅暴露的ADHD表型是确定DA基因型（DRD4，DRD5，DAT）和产生ADHD症状和损害的环境的相互作用的原型。在我们的网络中，我们在行为/现象学和动物模型遗传决定因素水平上开发了插值项目，以告知翻译“概念证明”临床试验。这项可行性试验将估计皮质 - 膜甲肾上腺素能（NE）释放药物Atomoxetine的效果大小。现在，使用直接DA激动剂/拮抗剂以及影响皮质 - limbic谷氨酸氨基氨基氨基氨基氨基氨基甲基神经元（CGN）电路（如atomoxetine）的间接药物，可以使用ADHD表型的药理学解剖。该提案的主要优势包括：1）网络成员之间的牢固，持续的协作关系； 2）关于在临床实践中遇到的非古典ADHD表型的新颖和可检验的假设，可以从中启动“概念证明”药理学试验； 3）一种具有良好特征且高度可利用的动物模型，可用于“ ADHD-TS表型的抗双歧性行为特征”的“电路测试”； 4）一个独特的机会，可以研究持续暴露的212名儿童的神经行为结局，当时该队列通常会发生ADHD的临床诊断，而通常发生ADHD的临床诊断； 5) examination of gene-environment interactions with DA-associated polymorphisms linked to ADHD phenotype expression, and 6) strong, extra-network linkages with the pediatric pharmacologic research units (PPRU) infrastructure, an animal model behavioral phenotyping laboratory, and a Howard Hughes Bioinformatics Center to expand on Arrant findings and "proof of concept' trials.