Centers for Intervention Development and Applied Research (CIDAR)

干预发展和应用研究中心 (CIDAR)

• 批准号: 8327303
• 负责人: William T. Carpenter
• 金额: $ 179.77万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327303
• 关键词: Address; Affect; Agonist; Animals; Applied Research; Biological; Clinical; Clinical Trials; Cognitive; Development; Drug Evaluation; Evaluation; Family; Human; Impaired cognition; Modeling; Molecular Target; Neurobehavioral Manifestations; Nicotinic Receptors; Oxytocin; Pathway interactions; Patients; Phenotype; Population; Psychopathology; Psychotic Disorders; Public Health; Rattus; Relative (related person); Schizophrenia; Stress; Symptoms; Techniques; Testing; Therapeutic; anabaseine; drug discovery; drug testing; functional outcomes; innovation; novel; novel strategies; pre-clinical; proband; research and development; therapy development

Schizophrenia is a major public health problem affecting almost 1% of the population with youthful onset of psychosis and poor functional outcomes. Personal, family, and societal impact is substantial. Two psychopathological domains, negative symptoms and cognitive impairments, typically preceed psychosis, and are robustly associated with poor functional outcome. No treatment has documented efficacy for these two domains. The purpose of the proposed studies is to advance drug discovery for these two domains using innovative evaluation platforms and testing drugs with novel molecular targets. Specific aims involve establishing innovative evaluation techniques and to determine the effect of a compound hypothesized to have efficacy for negative symptoms and a compound hypothesized to have efficacy for cognitive impairments. A second aim is to determine whether these two domains represent similar or separate developmental pathways for drug discovery. These aims will be accomplished by establishing three evaluation platforms: a] a pre-natal stress rat model which manifests phenotypes of both psychopathological domains; b] subjects selected from the biological relatives of schizophrenia probands who manifest phenotypes for both psychopathologies; and c] a clinical trials platform with schizophrenia subjects selected with phenotypic manifestations of the two psychopathologies. The two compounds chosen for testing are oxytocin for negative symptoms and 3-[(2,4-dimethoxy) benzylidene]anabaseine (DXMB-A), an alpha-7 nicotinic receptor partial agonist, for cognitive impairments. We will determine: a] the effect of each compound on both negative and cognitive phenotypes in each evaluation platform; b] whether effects in the pre-clinical and non-schizophrenia human models predicts effects in the clinical model; c] whether efficacy is observed in the clinical trial; and d] whether effects of each compound are specific for the hypothesized psychopathological domain. This project addresses the unmet therapeutic needs for schizophrenia by testing novel compounds for negative symptoms and cognitive impairments. Testing is performed on novel animal and human evaluation platforms in order to develop new approaches to early drug evaluation. Efficacy is determined in a clinical trial where patient subjects are selected according negative symptom and cognitive phenotypes.

精神分裂症是一个主要的公共卫生问题，影响着近 1% 的人口，其精神病在年轻时发病，功能结果较差。对个人、家庭和社会的影响是巨大的。阴性症状和认知障碍这两个精神病理学领域通常发生在精神病之前，并且与不良功能结果密切相关。目前尚无治疗方法对这两个领域的疗效有记录。拟议研究的目的是利用创新的评估平台和测试具有新分子靶点的药物来推进这两个领域的药物发现。具体目标包括建立创新的评估技术，并确定假设对阴性症状有效的化合物和假设对认知障碍有效的化合物的效果。第二个目标是确定这两个领域是否代表相似或独立的药物发现发展途径。这些目标将通过建立三个 评估平台：a]表现出两个精神病理领域表型的产前应激大鼠模型； b]从精神分裂症先证者的生物学亲属中选出的受试者，他们表现出两种精神病理学的表型； c] 一个临床试验平台，其中选择具有两种精神病理学表型表现的精神分裂症受试者。选择用于测试的两种化合物是用于治疗阴性症状的催产素和用于治疗认知障碍的 3-[(2,4-二甲氧基)亚苄基]anabaseine (DXMB-A)（一种 α-7 烟碱受体部分激动剂）。我们将确定： a] 每个评估平台中每种化合物对消极表型和认知表型的影响； b] 临床前和非精神分裂症人类模型中的效果是否可以预测临床模型中的效果； c] 临床试验中是否观察到疗效； d]每种化合物的作用是否对假设的精神病理学领域具有特异性。该项目通过测试新型化合物的阴性症状和认知障碍来解决精神分裂症未得到满足的治疗需求。在新动物上进行测试 和人类评估平台，以开发早期药物评估的新方法。疗效是在临床试验中确定的，其中根据阴性症状和认知表型选择患者受试者。

项目成果

The effects of oxytocin and galantamine on objectively-defined vocal and facial expression: Data from the CIDAR study.

催产素和加兰他敏对客观定义的声音和面部表情的影响：来自 CIDAR 研究的数据。

• DOI: 10.1016/j.schres.2017.01.028
• 发表时间: 2017-10
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Cohen AS;Mitchell KR;Strauss GP;Blanchard JJ;Buchanan RW;Kelly DL;Gold J;McMahon RP;Adams HA;Carpenter WT
• 通讯作者: Carpenter WT

Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia.

• DOI: 10.1016/j.schres.2016.02.014
• 发表时间: 2016-04
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Lee MR;Wehring HJ;McMahon RP;Liu F;Linthicum J;Verbalis JG;Buchanan RW;Strauss GP;Rubin LH;Kelly DL
• 通讯作者: Kelly DL

The involvement of Type II Neuregulin-1 in rat visuospatial learning and memory.

• DOI: 10.1016/j.neulet.2012.10.018
• 发表时间: 2012-12-07
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Taylor AR;Taylor SB;Koenig JI
• 通讯作者: Koenig JI

Corticotropin-releasing factor, serotonin, and sex: keys to the castle of depressive illness.

促肾上腺皮质激素释放因子、血清素和性：抑郁症城堡的钥匙。

• DOI: 10.1210/en.2009-0536
• 发表时间: 2009
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Koenig,JamesI

Endogenous oxytocin levels are associated with the perception of emotion in dynamic body expressions in schizophrenia.

• DOI: 10.1016/j.schres.2015.01.022
• 发表时间: 2015-03
• 期刊: SCHIZOPHRENIA RESEARCH
• 影响因子: 4.5
• 作者: Strauss, Gregory P.;Keller, William R.;Koenig, James I.;Sullivan, Sara K.;Gold, James M.;Buchanan, Robert W.
• 通讯作者: Buchanan, Robert W.