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Prospective Studies of the Pathogenesis of Schizophrenia

精神分裂症发病机制的前瞻性研究

基本信息

批准号：
8118883
负责人：
JOHN Horace GILMORE
金额：
$ 184.75万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8118883
关键词：
Prospective Studies Pathogenesis Schizophrenia

项目摘要

Schizophrenia has been considered a neurodevelopmental disorder for over two decades, yet the specific neurodevelopmental mechanisms that contribute to the cortical pathology central to schizophrenia remain unknown. Genetic vulnerability for schizophrenia has been recognized for almost 100 years; nevertheless, the relationship between genetic risk and specific neurodevelopmental mechanisms is unclear. The UNC Conte Center, "Prospective Studies of the Pathogenesis of Schizophrenia," will answer three key questions in an effort to synthesize neurodevelopmental mechanisms, genetic vulnerability, and the development of schizophrenia: 1) At what stage of development does cortical pathology arise in children at risk for schizophrenia? 2) How does cortical pathology contribute to the developmental expression of cognitive deficits and clinical symptoms of schizophrenia? and 3) Can an apparently diverse set of developmental mechanisms and risk genes give rise to a common cortical pathology implicated in schizophrenia? The central hypothesis of this competitive renewal of the UNC Conte Center is that genetic vulnerability for schizophrenia can compromise multiple mechanisms of early cortical development, each of which can ultimately contribute to aberrant cortical circuitry, neurocognitive deficits, and the clinical symptoms of schizophrenia. The clinical projects of the UNC Conte Center will use state-of-the-art multimodal imaging and image analysis to study the development of cortical structure and function in children at genetic high risk for schizophrenia during the two critical periods of cortical synaptic development: synaptic elaboration during early childhood (Project 1), and synaptic remodeling and elimination during adolescence (Project 2). In parallel, the preclinical projects will assess cortical precursor proliferation, neuronal migration and synapse formation in mouse models of three well characterized sets of risk genes: NCAM (Project 3); 22q11 genes (Project 4), and Neuregulin/Erb4 (Project 5). These projects will be supported by 3 cores - 1) Administrative, 2) Neuroimage Analysis 3) Biostatistics and Data Management; each part of the current Conte Center. Our goal is to synthesize clinical characterization of abnormal cortical structure and function in genetically vulnerable children with detailed assessment of abnormal neurodevelopmental mechanisms in the cortex of mice carrying mutations in specific risk genes. UNC Conte Center offers a focused, directed, and integrated set of clinical and basic projects and experiments that will identify fundamental mechanisms of cortical development that are the basis of the neurodevelopmental pathogenesis that is thought to underlie schizophrenia.

精神分裂症被认为是一种神经发育障碍超过二十年，但具体的神经发育机制，有助于大脑皮层病理中心精神分裂症仍然未知。精神分裂症的遗传易感性已经被认识了近100年;然而，遗传风险和特定神经发育机制之间的关系尚不清楚。康特中心，“精神分裂症发病机制的前瞻性研究”，将回答三个关键问题，努力综合神经发育机制，遗传脆弱性，精神分裂症的发展：1）在精神分裂症高危儿童中，皮质病理在哪个发育阶段出现？2)皮质病理学如何影响精神分裂症认知缺陷和临床症状的发展表达？和3）一组明显不同的发育机制和风险基因是否会引起与精神分裂症有关的常见皮质病理？这一竞争性的孔蒂中心更新的核心假设是，精神分裂症的遗传易感性可损害早期皮质发育的多种机制，每种机制最终可导致异常皮质回路、神经认知缺陷和精神分裂症的临床症状。康特中心的临床项目将使用最先进的多模态成像和图像分析来研究在皮质突触发育的两个关键时期，精神分裂症遗传高危儿童的皮质结构和功能的发展：幼儿期的突触发育（项目1），以及青春期的突触重塑和消除（项目2）。同时，临床前项目将评估三组风险基因的小鼠模型中的皮质前体增殖，神经元迁移和突触形成：NCAM（项目3）; 22 q11基因（项目4）和Neuregulin/Erb 4（项目5）。这些项目将由3个核心支持- 1）行政，2）神经影像分析，3）生物统计学和数据管理;目前康特中心的每个部分。我们的目标是综合临床表征遗传易感儿童的异常皮质结构和功能，详细评估携带特定风险基因突变的小鼠皮质异常神经发育机制。康特中心提供了一套集中，定向和综合的临床和基础项目和实验，这些项目和实验将确定皮质发育的基本机制，这些机制是被认为是精神分裂症的神经发育发病机制的基础。

项目成果

期刊论文数量（71）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development trends of white matter connectivity in the first years of life.

DOI：
10.1371/journal.pone.0024678
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Yap PT;Fan Y;Chen Y;Gilmore JH;Lin W;Shen D
通讯作者：
Shen D

Construction of multi-region-multi-reference atlases for neonatal brain MRI segmentation.

DOI：
10.1016/j.neuroimage.2010.02.025
发表时间：
2010-06
期刊：
NEUROIMAGE
影响因子：
5.7
作者：
Shi, Feng;Yap, Pew-Thian;Fan, Yong;Gilmore, John H.;Lin, Weili;Shen, Dinggang
通讯作者：
Shen, Dinggang

Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex.

DOI：
10.1016/j.acra.2011.08.016
发表时间：
2012-01
期刊：
ACADEMIC RADIOLOGY
影响因子：
4.8
作者：
Peters, Jurriaan M.;Sahin, Mustafa;Vogel-Farley, Vanessa K.;Jeste, Shafali S.;Nelson, Charles A., III;Gregas, Matthew C.;Prabhu, Sanjay P.;Scherrer, Benoit;Warfield, Simon K.
通讯作者：
Warfield, Simon K.

Brain anatomical networks in early human brain development.

人类早期大脑发育中的大脑解剖网络

DOI：
10.1016/j.neuroimage.2010.07.025
发表时间：
2011-02-01
期刊：
NEUROIMAGE
影响因子：
5.7
作者：
Fan, Yong;Shi, Feng;Smith, Jeffrey Keith;Lin, Weili;Gilmore, John H.;Shen, Dinggang
通讯作者：
Shen, Dinggang

Learning-based deformable image registration for infant MR images in the first year of life.

通过将随机森林与自动上下文模型相结合，进行基于学习的婴儿 MRI 变形配准