Adenosine and schizophrenia: mechanisms and therapies

腺苷和精神分裂症：机制和治疗

• 批准号: 7789636
• 负责人: Detlev Boison
• 金额: $ 33.15万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-20 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789636
• 关键词: Address; Adenosine; Adenosine A2A Receptor; Adenosine Kinase; Adverse effects; Affect; Agonist; Animals; Behavioral; Behavioral Assay; Biochemical; Biological; Biological Assay; Brain; Brain region; Corpus striatum structure; Development; Disease; Dopamine; Drug Delivery Systems; Engineering; Evaluation; Financial cost; Functional disorder; Future; Genetic; Glutamates; Hippocampus (Brain); Human; Individual; Infusion procedures; Intervention; Knockout Mice; Lead; Link; Mediating; Mental disorders; Modification; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurobehavioral Manifestations; Neuromodulator; Neurotransmitters; Outcome; Outcome Study; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Population; Positioning Attribute; Prosencephalon; Public Health; Purinergic P1 Receptors; Regulation; Relative (related person); Research; Role; Schizophrenia; Signal Transduction; Societies; Stem cells; Symptoms; System; Testing; Therapeutic; Transgenic Mice; Transplantation; Validation; Wild Type Mouse; base; behavior test; clinical efficacy; comparative; dopamine system; endophenotype; genetic manipulation; improved; in vivo; kinase inhibitor; neurochemistry; neuroregulation; neurotransmission; novel; novel strategies; overexpression; psychopharmacologic; public health relevance; receptor; receptor function; relating to nervous system; research study; social; theories

DESCRIPTION (provided by applicant): Adenosine and schizophrenia: mechanisms and therapies Project Summary: Schizophrenia (SZ) is a debilitating mental illness with tremendous human, social and financial costs to society. Unfortunately, existing treatments are unsatisfactory and current development remains stagnant due to poor understanding of the biological bases of the disease. Two perspectives have emphasized disturbances in two neurochemical messengers in the brain -dopamine and glutamate, in relation to disparate SZ- symptoms. This proposal will examine a third messenger -adenosine (ADO), as a potential link uniting the dopamine and glutamate hypotheses of SZ. ADO can regulate both dopamine and glutamate neurotransmission via receptors with opposing actions (A1 vs. A2A adenosine receptors). ADO is therefore uniquely positioned as an upstream coordinator/regulator between these two neurotransmitter systems. Hence, ADO-based treatment may be an attractive alternative with dual corrective actions on the glutamate and dopamine systems, thereby achieving effective control over selected SZ symptoms. Our central hypothesis is that subtle disturbances in adenosinergic neuromodulation can give rise to selected behavioral endophenotypes implicated in SZ; thus corresponding corrective interventions targeting at the ADO system should confer therapeutic potential against such SZ endophenotypes, and thereby validate our hypothesis. Our hypothesis will be tested by three specific aims. First, we will characterize the emergence of selected SZ-related endophenotypes as well as their opposing phenotypes in transgenic mice with either over- or under- expression of brain ADO achieved by genetic manipulation of adenosine kinase. Second, we aim to identify the molecular mechanisms of adenosine-based modulation of dopaminergic and glutamatergic neurotransmission. This will be achieved by behavioral and biochemical examination of A1R and A2AR knockout mice. Third, we aim to dissect the brain regions in which ADO-dopamine interactions and ADO-glutamate interactions contribute to the regulation of specific SZ-related endophenotypes. To achieve this, ADO will locally be modified by transplantation of ADO-secreting stem cells and by focal infusion of drugs acting on ADO-receptors. The expected outcomes of this project include: (i) the biological validation of a novel neurochemical theory of SZ, and (ii) the feasibility-test of a novel ADO-based strategy to produce behavioral adjustment with therapeutic potential. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating mental disorder to the individual and society alike, yet the efficacy of current drug treatment remains poor, and the development of novel drugs is limited to either blocking dopamine or enhancing glutamate neurotransmission. This proposal will examine a novel drug target for schizophrenia-therapy -adenosine: Given adenosine's unique position to interact in parallel with dopamine and glutamate neurotransmission, adenosine-modulating drugs are hypothesized to confer therapeutic potential against multiple SZ symptoms.

描述（由申请人提供）： 腺苷和精神分裂症：机制和治疗 项目概要： 精神分裂症 (SZ) 是一种使人衰弱的精神疾病，给社会带来巨大的人力、社会和财政成本。不幸的是，由于对该疾病的生物学基础了解甚少，现有的治疗方法并不令人满意，并且目前的发展仍然停滞不前。有两种观点强调大脑中两种神经化学信使——多巴胺和谷氨酸的紊乱，与不同的 SZ 症状相关。该提案将研究第三个信使 - 腺苷 (ADO)，作为联合 SZ 的多巴胺和谷氨酸假说的潜在联系。 ADO 可以通过具有相反作用的受体（A1 与 A2A 腺苷受体）调节多巴胺和谷氨酸神经传递。因此，ADO 被独特地定位为这两个神经递质系统之间的上游协调器/调节器。因此，基于 ADO 的治疗可能是一种有吸引力的替代方案，对谷氨酸和多巴胺系统具有双重纠正作用，从而实现对选定的 SZ 症状的有效控制。我们的中心假设是，腺苷能神经调节的微妙干扰可以引起与 SZ 相关的选定行为内表型；因此，针对 ADO 系统的相应纠正干预措施应该具有针对此类 SZ 内表型的治疗潜力，从而验证我们的假设。我们的假设将通过三个具体目标进行检验。首先，我们将描述转基因小鼠中选定的 SZ 相关内表型的出现及其相反的表型，这些转基因小鼠通过腺苷激酶的基因操作实现脑 ADO 的过度或不足表达。其次，我们的目标是确定基于腺苷的多巴胺能和谷氨酸能神经传递调节的分子机制。这将通过 A1R 和 A2AR 敲除小鼠的行为和生化检查来实现。第三，我们的目标是剖析 ADO-多巴胺相互作用和 ADO-谷氨酸相互作用有助于调节特定 SZ 相关内表型的大脑区域。为了实现这一目标，ADO 将通过移植 ADO 分泌干细胞和局部输注作用于 ADO 受体的药物进行局部修饰。该项目的预期成果包括：(i) 对 SZ 的新型神经化学理论进行生物学验证，以及 (ii) 对基于 ADO 的新型策略进行可行性测试，以产生具有治疗潜力的行为调整。公共卫生相关性：精神分裂症对个人和社会来说都是一种毁灭性的精神障碍，但目前药物治疗的效果仍然很差，新药的开发仅限于阻断多巴胺或增强谷氨酸神经传递。该提案将研究精神分裂症治疗的新药物靶点——腺苷：鉴于腺苷与多巴胺和谷氨酸神经传递平行相互作用的独特地位，腺苷调节药物被认为具有针对多种精神分裂症症状的治疗潜力。