Centers for Intervention Development and Applied Research (CIDAR)

干预发展和应用研究中心 (CIDAR)

• 批准号: 7690198
• 负责人: William T. Carpenter
• 金额: $ 199.82万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690198
• 关键词: Centers; Intervention; Development; Applied; Research

DESCRIPTION (provided by applicant): Project 1: Evaluation of Oxytocin in the Prenatal Stress Animal Model of Schizophrenia (PI: Dr. James Koenig). Drug discovery for schizophrenia has been oriented towards psychosis, but primary negative symptoms and the cognitive impairments are robustly associated with poor functional outcomes. This CIDAR application embraces the notion that novel preclinical and clinical approaches are necessary for the development of new therapies for the negative symptom and cognitive impairment domains of schizophrenia. We have generated a novel pre-clinical animal preparation based on developmental and epidemiological data showing that mid-gestational stress exposure increases the risk for developing schizophrenia. This preclinical model is ideally suited to launch a translational investigation of novel drugs for use in treating schizophrenia. Exciting pre-clinical findings from the use of this model form the basis for studying oxytocin's effects in clinical and pre-clinical models of the negative symptoms of schizophrenia, as proposed in this CIDAR application and in Projects #1, 2 and 3. Additionally, this preclinical model will be used to evaluate whether significant clinical findings regarding the alpha? nicotinic receptor and cognition can be extended to the pre-clinical situation. The overall hypothetical framework for this CIDAR application is based on the following propositions: 1) that negative symptoms and cognitive impairments may be separate clinical targets for drug development, and a 0drug with efficacy for one domain may not have an effect on the other; 2) that a drug effect on a domain in a clinical trial will be associated with a similar effect in a pre-clinical rat model and a non-clinical human model and 3) that oxytocin receptor stimulation and alpha-7 nicotinic receptor stimulation will benefit behaviors elating to the negative symptoms and cognitive impairments of schizophrenia, respectively. We will examine the following hypotheses in the pre-clinical rat model: hypothesis 1 A: oxytocin will improve behaviors related to the negative symptoms of schizophrenia but not the cognitive impairments in the pre-clinical rat model of schizophrenia. Hypothesis 1B: improvement of social function in the pre-clinical rat model will be accompanied by normalization of oxytocin mRNA production and receptor function. Hypothesis 2A: alpha-7 nicotinic receptor stimulation with DMXB-A, an alpha-7 nicotinic receptor partial agonist, will improve cognition in the pre-clinical rat model but not behavioral assays related to the negative symptoms of the disease. Hypothesis 2B: improvements in cognition will be accompanied by increased expression of alpha-7 nicotinic receptors in the hippocampus of the rat pre-clinical model. Data from this Project will also be used to address the overall CIDAR hypotheses.

描述（由申请人提供）：项目1：催产素在精神分裂症产前应激动物模型中的评价（PI：James Koenig博士）。精神分裂症的药物发现一直以精神病为导向，但原发性阴性症状和认知障碍与不良功能结局密切相关。该CIDAR申请包含了新的临床前和临床方法对于开发精神分裂症阴性症状和认知障碍领域的新疗法是必要的这一概念。我们已经产生了一种新的临床前动物准备的基础上发展和流行病学数据显示，中期妊娠应激暴露增加患精神分裂症的风险。这种临床前模型非常适合启动用于治疗精神分裂症的新药的转化研究。令人兴奋的临床前研究结果从使用这个模型形成的基础上研究催产素的影响，在临床和临床前模型的阴性症状的精神分裂症，提出在这个CIDAR应用程序和项目#1，2和3。此外，该临床前模型将用于评价是否有关于α？烟碱受体与认知的关系可以扩展到临床前的情况。 CIDAR应用的总体假设框架基于以下命题：1）阴性症状和认知障碍可能是药物开发的独立临床靶点，对一个领域有效的药物可能对另一个领域没有影响; 2）在临床试验中对一个域的药物作用将与在临床前大鼠模型和非临床人类模型中的类似作用相关，以及3）催产素受体刺激和α-7烟碱受体刺激将分别有益于与精神分裂症的阴性症状和认知障碍相关的行为。我们将在临床前大鼠模型中检验以下假设：假设1A：催产素将改善与精神分裂症阴性症状相关的行为，但不会改善精神分裂症临床前大鼠模型中的认知障碍。假设1B：临床前大鼠模型中社会功能的改善将伴随着催产素mRNA产生和受体功能的正常化。假设2A：用DMXB-A（α-7烟碱受体部分激动剂）刺激α-7烟碱受体将改善临床前大鼠模型中的认知，但不改善与该疾病的阴性症状相关的行为测定。假设2B：认知的改善将伴随着大鼠临床前模型海马体中α-7烟碱受体表达的增加。该项目的数据也将用于解决总体CIDAR假设。