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An Interdisciplinary program for systems genomics of complex behaviors

复杂行为系统基因组学跨学科项目

基本信息

批准号：
7932971
负责人：
Fernando Pardo-Manuel de Villena
金额：
$ 297.76万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7932971
关键词：
Address Adverse reactions Algorithms Alleles Antipsychotic Agents Anxiety Area Autistic Disorder Behavior Behavioral Biological Biology Biomedical Research Breeding Cessation of life Chromosome Mapping Clozapine Collection Commit Communities Complement Complex Computational Biology Copy Number Polymorphism Data Data Collection Data Set Databases Development Discipline Disease Disease model Dissection Environment Environmental Impact Etiology Funding Future Gene Expression Profile Genes Genetic Genetic Models Genetic Variation Genome Genomics Genotype Goals Haloperidol Head Human Human Genetics Imagery Institution Intention Joints Knowledge Laboratory Organism Language Length Major Depressive Disorder Mental Depression Mental disorders Meta-Analysis Minority Minority Groups Modeling Molecular Morbidity - disease rate Motivation Mouse Strains Mus National Human Genome Research Institute National Institute of Mental Health Parents Pathway interactions Performance Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Pilot Projects Policies Population Preparation Principal Investigator Probability Production Psychiatry Public Health Randomized Reaction Recombinants Recording of previous events Regulation Research Research Personnel Research Support Resource Sharing Resources Risk Sample Size Schizophrenia Science Scientist Social Behavior Societies Stress System Systems Biology TNFRSF5 gene Testing Time Training Underrepresented Minority United States National Institutes of Health Variant Work X Inactivation Yeasts computer science computerized data processing cost data management data sharing design environmental enrichment for laboratory animals expectation genetic resource genome wide association study genome-wide high risk imprint innovation knowledge base mammalian genome metabolomics model development molecular phenotype mortality mouse model novel panacea phenome predictive modeling programs public health relevance sex success tool trait user-friendly

项目摘要

DESCRIPTION (provided by applicant): In this application, we propose a highly ambitious yet realistically attainable goal: to align existing expertise at UNC-CH into a center of excellence in order to develop as a resource and demonstrate the utility of the murine Collaborative Cross (CC) to delineate genetic and environmental determinants of complex phenotypes drawn from psychiatry, the most intractable set of problems in all of biomedicine. We propose a particularly challenging definition of success - we will identify high probability etiological models (which can be realistically complex) and then prove the predictive capacity of these models by generating novel strains of mice bred to be at either very low or very high risk of the phenotype. Once validated, these high confidence models can then be tested in subsequent human studies. The data collected at the UNC center would be a valuable resource to the wider scientific community and could be used to interrogate any number of biological problems. The development of sophisticated, user-interactive databases to access the large, complex datasets collected represents a key component of the project. Accomplishing this overarching goal requires an exceptional diversity of scientific expertise - psychiatry, human genetics, mouse phenotyping, mouse genetics, statistical genetics, computational biology, and systems biology. Experts in all of these disciplines were deeply involved in the preparation of this application and are committed to the projects described here. Moreover, successful integration of these diverse fields is non-trivial; however, we can document that all scientists on this application have a history of extensive interactions over the past five years, know now how to work together and have a working knowledge of their colleagues' expertise. UNC-Chapel Hill has a shown an intense commitment to promoting inter-disciplinary genomics research and is one of the most collegial biomedical research institutions in the US which provides a fertile backdrop for "Science 2.0" projects such as that proposed here. PUBLIC HEALTH RELEVANCE Psychiatric disorders are a paradox-the associated morbidity, mortality, and societal costs are enormous and yet, despite over a century of scientific study, there are few hard facts about the etiology of the core diseases. Although GWAS meta-analyses are in progress, early results suggest that strong and replicable findings are elusive. Our proposal provides an alternative model approach to complement the study of fundamental psychiatric phenotypes.

描述(由申请人提供)：在本申请中，我们提出了一个非常雄心勃勃但现实可实现的目标：将北卡罗来纳大学-CH分校的现有专业知识结合成一个卓越的中心，以开发作为一种资源，并展示小鼠合作交叉(CC)的效用，以描绘来自精神病学的复杂表型的遗传和环境决定因素，这是所有生物医学中最棘手的一组问题。我们提出了一个特别具有挑战性的成功定义--我们将识别高概率病因模型(实际上可能很复杂)，然后通过产生新的小鼠品系来证明这些模型的预测能力，这些品系被培育成具有非常低或非常高的表型风险。一旦得到验证，这些高置信度模型就可以在随后的人体研究中进行测试。北卡罗来纳大学中心收集的数据将是更广泛的科学界的宝贵资源，可以用来询问任何数量的生物问题。开发复杂的用户交互数据库以访问收集的大型、复杂的数据集是该项目的一个关键组成部分。要实现这一首要目标，需要拥有丰富多样的科学专业知识--精神病学、人类遗传学、小鼠表型鉴定、小鼠遗传学、统计遗传学、计算生物学和系统生物学。所有这些学科的专家都深度参与了本申请的准备工作，并致力于这里所述的项目。此外，这些不同领域的成功整合并不是微不足道的；然而，我们可以证明，在这一应用程序中的所有科学家在过去五年中都有广泛的互动历史，现在知道如何合作，并对他们同事的专业知识有所了解。北卡罗来纳大学教堂山分校表现出对促进跨学科基因组学研究的强烈承诺，是美国最具合作精神的生物医学研究机构之一，为这里提出的“科学2.0”项目提供了肥沃的背景。公共卫生相关性精神障碍是一个悖论--相关的发病率、死亡率和社会成本是巨大的，然而，尽管进行了一个多世纪的科学研究，但关于核心疾病的病因学几乎没有确凿的事实。尽管GWAS的荟萃分析正在进行中，但早期的结果表明，强有力和可复制的发现是难以捉摸的。我们的建议提供了一种替代模型方法来补充基础精神表型的研究。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Detecting major genetic loci controlling phenotypic variability in experimental crosses.

DOI：
10.1534/genetics.111.127068
发表时间：
2011-06
期刊：
Genetics
影响因子：
3.3
作者：
Rönnegård L;Valdar W
通讯作者：
Valdar W

A statistical framework for eQTL mapping using RNA-seq data.

DOI：
10.1111/j.1541-0420.2011.01654.x
发表时间：
2012-03
期刊：
Biometrics
影响因子：
1.9
作者：
Sun W
通讯作者：
Sun W

Genetic architecture of skewed X inactivation in the laboratory mouse.

DOI：
10.1371/journal.pgen.1003853
发表时间：
2013
期刊：
PLoS genetics
影响因子：
4.5
作者：
Calaway JD;Lenarcic AB;Didion JP;Wang JR;Searle JB;McMillan L;Valdar W;Pardo-Manuel de Villena F
通讯作者：
Pardo-Manuel de Villena F

Brain levels of the neurotoxic pyridinium metabolite HPP+ and extrapyramidal symptoms in haloperidol-treated mice.

DOI：
10.1016/j.neuro.2013.09.005
发表时间：
2013-12
期刊：
NEUROTOXICOLOGY
影响因子：
3.4
作者：
Crowley, James J.;Ashraf-Khorassani, Mehdi;Castagnoli, Neal, Jr.;Sullivan, Patrick F.
通讯作者：
Sullivan, Patrick F.

Chapter 10: Mining genome-wide genetic markers.