Mechanism-based, pro-cognitive therapies for schizophrenia

描述(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，如社交孤立和情感平淡；以及认知症状，包括注意力和工作记忆受损。这些认知缺陷构成了这种疾病的核心组成部分，往往会阻止精神分裂症患者融入社会。目前可用的抗精神病治疗在改善精神分裂症的阳性症状方面是有效的。然而，这些药物往往会导致严重的副作用，在治疗这种疾病的阴性症状或认知症状方面效果不佳，因此是一种主要的未得到满足的医疗需求。缺乏更有效的精神分裂症治疗的一个主要原因是我们对疾病背后的分子机制缺乏了解。基于我们对前脑特异的钙调神经磷酸酶基因敲除小鼠的功能和行为特征的描述，我们为精神分裂症的认知缺陷发展了一种新的疾病假说，在这种疾病中，突触小泡循环的中断会导致支持工作记忆所必需的前额叶皮质神经元和网络活动的损害。这些数据与越来越多的来自多种实验模式的发现相一致，这些发现表明突触前功能改变与精神分裂症的病因有关。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括有效治疗精神分裂症认知症状的药物。为了创造一种识别具有这种所需性质的化合物的方法，我们设计并构建了一种新的突触前高通量筛选技术，利用该技术，我们可以在96孔板上分析化合物对神经元培养中突触小泡循环的影响。这项建议的目的是利用这一新的技术平台来筛选化合物文库，识别突触囊泡循环的调节器，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铅优化的成熟阶段。在实现这项提议的科学目标后，我们打算与一家大型制药公司合作平台技术和鉴定化合物，以加快这一计划的进一步推进。拟议研究的完成将直接有助于开发一种新的、一流的、基于机制的治疗精神分裂症认知症状的方法。这一进展将对精神分裂症患者及其家人的生活产生重大积极影响。此外，这项提案支持经济刺激的使命，为多名科学家提供新的工作机会，并支持新技术的出现和随后新类别有价值的医药产品的开发。 公共卫生相关性：我们发现了精神分裂症认知缺陷的一种新的疾病机制。基于这一发现，我们开发了一种新的筛选技术，利用该技术，我们可以识别治疗精神分裂症的新类别候选药物。特别是，这项提案中概述的研究将支持为精神分裂症的认知缺陷确定新的治疗方法，这是一个主要的未得到满足的医疗需求。因此，这项研究将对包括全球数百万人在内的大量精神分裂症患者及其家人和照顾者产生积极影响。特别是，改善精神分裂症患者的认知结果将有助于患者提高工作表现，更有效地融入社会。

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.