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)：我们的网络小组寻求将神经科学家、遗传学家、药理学家、儿科医生和儿童精神病学家的合作正规化，以便通过专注于非临床表型来超越我们目前对ADHD病因学概念化的限制。非经典表型的选择是基于它们共同的涉及回路的病理生理学，该回路适用于动物模型和临床中的行为和药物解剖的“回路测试”。这些ADHD表型包括以多巴胺能(DA)病理生理学为核心特征，并在症状产生中共享共同的皮质-边缘谷氨酸能神经元(CGN)回路。每一种表型都具有启发式的价值，不仅可以通过识别共同的机制来理解ADHD的“异常值”，还可以理解经典的ADHD。我们假设的一种共享机制是关键的皮质-边缘通路的谷氨酸能价态(Carlsson 2000)。我们建议将铅暴露的ADHD表型作为一个原型，以确定DA基因(DRD4、DRD5、DAT)与产生ADHD症状和损害的环境之间的相互作用。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干预项目，以提供翻译的“概念证明”临床试验。这项可行性试验将评估皮质-边缘去甲肾上腺素(NE)释放药物托莫西汀的效应大小。现在，使用直接的DA激动剂/拮抗剂以及影响皮质-边缘谷氨酸能神经元(CGN)回路的间接药物，如托莫西汀，可以对ADHD的表型进行药理学解剖。这一建议的主要优势包括：1)网络成员之间强大的、持续的合作关系；2)关于临床实践中遇到的非经典ADHD表型的新颖且可检验的假说，由此可以启动“概念验证”药理学试验；3)具有良好特征且高度可用于ADHD-TS表型对足部行为特征的“电路测试”的动物模型；4)随着队列达到临床诊断ADHD通常发生的时间(学龄段)，研究212名持续接触铅的儿童的神经行为结果的独特机会；5)检测与ADHD表型表达相关的DA相关多态与基因-环境的相互作用，以及6)与儿科药理研究单位(PPRU)基础设施、动物行为表型实验室和Howard Hughes生物信息学中心建立强大的网络外联系，以扩展重大发现和“概念验证”试验。