Mechanism-based, pro-cognitive therapies for schizophrenia

描述（由申请人提供）：精神分裂症是一种使人衰弱的精神疾病，影响全球约0.7%的人口。精神分裂症的症状可分为三类：阳性症状，包括幻觉和妄想；消极症状，如社交孤立和情绪低落；认知症状，包括注意力和工作记忆受损。这些认知缺陷是该疾病的一个核心组成部分，往往阻碍精神分裂症患者融入社会。目前可用的抗精神病药物在改善精神分裂症阳性症状方面是有效的。然而，这些药物往往会造成严重的副作用，对治疗该病的阴性症状或认知症状无效，因此这是一个未得到满足的主要医疗需求。缺乏更有效的精神分裂症治疗方法的一个主要原因是我们对这种疾病的分子机制了解不足。基于我们对前脑特异性钙调磷酸酶敲除小鼠的功能和行为特征，我们为精神分裂症的认知缺陷提出了一种新的疾病假设，其中突触囊泡循环的破坏导致前额皮质中支持工作记忆所必需的神经元和网络活动的损害。这些数据与越来越多来自多种实验模式的发现一致，表明突触前功能的改变有助于精神分裂症的病因学。我们的假设预测，能够恢复异常神经元突触前功能的化合物应该包含对精神分裂症认知症状的有效治疗。为了创建一种方法来鉴定具有这种期望特性的化合物，我们设计并构建了一种新的突触前高通量筛选技术，通过该技术我们可以分析96孔板中神经元培养中化合物对突触囊泡循环的影响。本课题的目标是利用这一新的技术平台筛选化合物库，鉴定突触囊泡循环的调节剂，并推进选定的化合物系列，以实现相关动物模型的概念验证和先导物优化的成熟阶段。在实现本提案的科学目标后，我们打算与一家大型制药公司合作开发平台技术和鉴定化合物，以加快该计划的进一步推进。这项研究的完成将直接有助于开发一种新型的、一流的、基于机制的精神分裂症认知症状治疗方法。这一进展将对精神分裂症患者及其家庭成员的生活产生重大的积极影响。此外，该提案通过为多位科学家提供新的就业机会，支持新技术的出现和新一类有价值的医药产品的后续开发，从而支持经济刺激的使命。

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating psychiatric disorder that affects about 0.7% of the global population. Symptoms of schizophrenia can be grouped into three categories: positive symptoms, including hallucinations and delusions; negative symptoms, such as social isolation and flattened affect; and cognitive symptoms, which include impaired attention and working memory. These cognitive deficits comprise a core component of the disease and often prevent schizophrenia patients from integrating into society. Currently available antipsychotic therapies are effective at ameliorating positive symptoms of schizophrenia. However, these drugs often cause serious side effects and are not effective at treating the negative or cognitive symptoms of the disease, which thus represent a major unmet medical need. A primary reason for the lack of more effective treatments for schizophrenia is our poor understanding of the molecular mechanisms underlying the disease. Based upon our functional and behavioral characterization of the forebrain-specific calcineurin knockout mouse, we have developed a novel disease hypothesis for the cognitive deficits of schizophrenia in which a disruption of synaptic vesicle cycling leads to impairments of the neuronal and network activities in prefrontal cortex that are necessary to support working memory. These data are in line with an increasing number of findings from multiple experimental modalities indicating that altered presynaptic function contributes to the etiology of schizophrenia. Our hypothesis predicts that compounds that can restore aberrant neuronal presynaptic function should comprise effective therapies for the cognitive symptoms of schizophrenia. To create a method for identifying compounds with this desired property, we have designed and constructed a novel presynaptic high throughput screening technology with which we can analyze the effects of compounds on synaptic vesicle cycling in neuronal cultures in 96-well plates. The objective of this proposal is to utilize this new technology platform to screen a library of compounds, identify modulators of synaptic vesicle cycling and advance selected compound series to achievement of proof-of-concept in relevant animal models and a mature stage of lead optimization. Upon achievement of the scientific goals of this proposal, we intend to partner the platform technology and identified compounds with a large pharmaceutical corporation to expedite further advancement of this program. Accomplishment of the proposed research will directly contribute to the development of a novel, first-in-class, mechanism-based therapy for the cognitive symptoms of schizophrenia. This advance would have a major positive impact on the lives of schizophrenia patients and their family members. In addition, this proposal supports the mission of economic stimulus by providing new jobs for multiple scientists and supporting the emergence of a new technology and the subsequent development of a new class of valuable medicinal products. PUBLIC HEALTH RELEVANCE: We have discovered a new disease mechanism for the cognitive deficits in schizophrenia. Based on this finding, we have developed a novel screening technology with which we can identify new classes of candidate drugs for treatment of schizophrenia. In particular, the research outlined in this proposal will support the identification of new therapies for the cognitive deficits in schizophrenia, which comprise a major unmet medical need. This research will thus have a positive impact on the significant population of schizophrenia patients and their family members and caregivers, which includes many millions of people worldwide. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their job performance and to integrate into society more effectively.