Prospective Studies of the Pathogenesis of Schizophrenia

精神分裂症发病机制的前瞻性研究

• 批准号: 6655113
• 负责人: JEFFREY A. LIEBERMAN
• 金额: $ 184.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655113
• 关键词: Prospective; Studies; Pathogenesis; Schizophrenia

DESCRIPTION (provided by applicant): The proposed UNC-CCNMD is a multidisciplinary organization comprised of scientists from the University of North Carolina, Duke, Harvard and the University of Washington directed by Dr. Jeffrey Lieberman, a research psychiatrist whose career has focused on the natural history and neurobiology of schizophrenia. The proposed center consists of 3 projects and 2 cores. The general aim of the UNC-CCNMD is to identify predictors of onset of schizophrenia and the underlying pathology in neurodevelopmental mechanisms that mediate disease vulnerability and expression. Although schizophrenia is believed to be a genetically mediated neurodevelopmental disorder, there is little clinical research demonstrating early abnormalities in brain structure and function and no definitive data identifying risk genes. Moreover, studies have neither identified causal neurobiologic mechanisms nor linked them to the natural history and clinical onset of the disease. Symptoms of schizophrenia emerge predominantly between the ages of 15 and 25 years. Thus, neurodevelopmental events in adolescence may be targets of pathogenic processes that contribute to disease vulnerability and expression. We hypothesize that schizophrenia vulnerability and expression arises from the consequences of dysconnectivity in thalamo-limbic-cortical circuits (TLC) due to disrupted differentiation of cortical GABA neurons and the cellular elements with which they modulate local cortical circuitry. These developmental anomalies in GABA interneurons confer vulnerability that when acted on by ontogenetic and environmental events during adolescence trigger dysfunction in TLC circuits and disease expression. 2 clinical and 2 preclinical projects will address this hypothesis. The clinical projects are prospective longitudinal studies of 2 unique high-risk populations enriched for the development of schizophrenia: adolescents and young adults with prodromal signs (Project 1) and fetuses and neonates of parents with schizophrenia (Project 2). The preclinical project involves a study of cell biological mechanisms of dendritic and axonal development in cortical GABA neurons as well as consequences of mutations in suspected vulnerability genes on this process (Project 3). Thus, the UNC-CCNMD is distinguished by its focus on behavioral and neurobiologic mechanisms that lead to the onset of the disease rather than clinical or pathologic correlates that emerge once it has been diagnosed. Our results will contribute to the identification of diagnostic methods and novel targets for intervention prior to the clinical deterioration that characterizes schizophrenia. In this way the Center will not only advance the neuroscience of schizophrenia but will have an immediate impact on the clinical care and treatment of persons who have and are at risk for schizophrenia.

描述（由申请人提供）：拟议的UNC-CCNMD是一个多学科组织，由来自北卡罗来纳州、杜克、哈佛和华盛顿大学的科学家组成，由杰弗里·利伯曼博士领导，他是一名研究精神病学家，其职业生涯主要集中在精神分裂症的自然史和神经生物学方面。拟建中心由3个项目和2个核心组成。UNC-CCNMD的总体目标是确定精神分裂症发作的预测因素以及介导疾病脆弱性和表达的神经发育机制中的潜在病理学。虽然精神分裂症被认为是一种遗传介导的神经发育障碍，但很少有临床研究表明大脑结构和功能的早期异常，也没有确定的数据识别风险基因。此外，研究既没有确定因果神经生物学机制，也没有将其与疾病的自然史和临床发病联系起来。精神分裂症的症状主要出现在15至25岁之间。因此，青春期的神经发育事件可能是致病过程的目标，有助于疾病的脆弱性和表达。我们假设，精神分裂症的脆弱性和表达所产生的后果，在丘脑-边缘-皮质电路（TLC），由于破坏分化的皮质GABA神经元和细胞的元素，他们调制当地的皮质电路的连接障碍。GABA中间神经元的这些发育异常赋予脆弱性，当青春期个体发育和环境事件触发TLC电路和疾病表达功能障碍时。2个临床和2个临床前项目将解决这一假设。临床项目是对2个独特的精神分裂症高危人群进行的前瞻性纵向研究：有前驱体征的青少年和年轻人（项目1）和父母患有精神分裂症的胎儿和新生儿（项目2）。临床前项目涉及研究皮层GABA神经元中树突和轴突发育的细胞生物学机制，以及疑似脆弱性基因突变对这一过程的影响（项目3）。因此，UNC-CCNMD的区别在于它关注导致疾病发作的行为和神经生物学机制，而不是一旦被诊断出来就出现的临床或病理相关性。我们的研究结果将有助于识别诊断方法和新的目标，在临床恶化之前，精神分裂症的特点进行干预。通过这种方式，该中心不仅将推进精神分裂症的神经科学，而且将对患有精神分裂症和有精神分裂症风险的人的临床护理和治疗产生直接影响。