Project 2

项目2

• 批准号: 9978139
• 负责人: Mikhail V Pletnikov
• 金额: $ 46.67万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-12 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978139
• 关键词: Adolescence; Adolescent; Adrenal Glands; Adult; Behavior; Behavioral; Biological Markers; Blood specimen; Brain; Cell model; Cognitive deficits; Collaborations; Complement 1q; Copy Number Polymorphism; DISC1 gene; DNA Sequence Alteration; Data; Data Set; Dendritic Spines; Development; Diagnosis; Dimensions; Disease; Dopamine; Environmental Risk Factor; Expression Profiling; Future; Gene Expression; Gene Expression Profiling; Genes; Goals; Human; Hypothalamic structure; Impairment; Innate Immune Response; Interneurons; Knockout Mice; Measures; Medial; Mental disorders; Microtubules; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neurons; Onset of illness; Oxidative Stress; Parvalbumins; Peripheral; Pharmaceutical Preparations; Phenotype; Pituitary Gland; Predisposition; Prefrontal Cortex; Prognostic Marker; Prospective cohort; Psychotic Disorders; Publishing; RNA; Role; Sampling; Schizophrenia; Social isolation; Stress; Symptoms; System; Testing; base; behavioral phenotyping; behavioral study; biological adaptation to stress; case control; cognitive function; cohort; conditional knockout; experimental study; frontal lobe; gene environment interaction; genetic risk factor; genetic variant; high risk; hippocampal pyramidal neuron; malformation; mind control; mouse model; mutant; neurobehavioral; peripheral blood; prognostic; social stress; transcriptome; transcriptome sequencing; young adult

The main goal of the current proposal is to identify the molecular and neurobehavioral abnormalities in young adulthood resulting from the genetic mutations of the microtubule-related genes associated with schizophrenia (SZ), such as PCM1, DPYSL2, and 16p11 copy number variations (CNVs), and how these alterations can be exacerbated by adolescent social isolation to produce a full-blown psychiatric disorder in young adulthood. We hypothesize that mice with the microtubule-associated genetic mutations will display stress-related molecular alterations and abnormal prefrontal cortex (PFC) maturation during adolescence and/or young adulthood, leading to adult behavioral phenotypes resembling different dimensions of SZ. Aim 1 will identify the genetic mutations-produced neurobehavioral abnormalities that can be exacerbated by adolescent social isolation in mice. We will identify the effects of the genetic risk factors on SZ-related behaviors as well as maturation of GABAergic interneurons and dendritic spines of pyramidal neurons in the PFC. We will also examine if these phenotypes are exacerbated by adolescent social isolation. Aim 2 will determine the genetic mutations- produced molecular changes that can be intensified by adolescent social isolation. Specifically, we will evaluate expression of the candidate stress-related factors and the global transcriptome changes in PFC. Aim 3 will identify alterations in stress-associated molecules in peripheral blood samples collected from two independent prospective cohorts and compare the human results with those from the mouse models. The project will determine alteration in stress-related molecular expression induced by genetic mutations, leading to impaired PFC maturation during adolescence and adult behavioral consequences, which may underlie susceptibility to detrimental effects of adolescent social isolation. Our project will facilitate future development of prognostic measures and biomarkers to help identify prodromal signs of the disease.

目前这项提议的主要目标是确定年轻人的分子和神经行为异常。 精神分裂症相关微管相关基因基因突变导致的成年期 (SZ)，如PCM1、DPYSL2和16p11拷贝数变异(CNV)，以及这些改变如何 由于青少年的社交孤立而加剧，在青壮年时会产生全面的精神障碍。我们 假设具有微管相关基因突变的小鼠将显示与应激相关的分子 青春期和/或青春期的变化和前额叶皮质(PFC)的异常成熟， 导致成人行为表型类似于不同维度的SZ。目标一号将确定基因 突变导致的神经行为异常，青少年社交孤立会加剧这种异常 老鼠。我们将确定遗传危险因素对SZ相关行为的影响以及SZ相关行为的成熟 前额叶内GABA能中间神经元和锥体神经元的树突棘。我们还将检查这些是否 青少年的社交孤立会加剧他们的表型。目标2将确定基因突变- 产生了分子变化，这种变化可能会因青少年的社交孤立而加剧。具体来说，我们将 评估PFC中候选应激相关因子的表达和整体转录组的变化。目标 3将确定从两个人采集的外周血液样本中应激相关分子的变化 独立的前瞻性队列，并将人类结果与小鼠模型的结果进行比较。这个 该项目将确定由基因突变诱导的压力相关分子表达的变化，导致 青春期PFC成熟受损和成人行为后果，这可能是基础 容易受到青少年社交孤立的不利影响。我们的项目将促进未来的发展 预后措施和生物标志物，以帮助识别疾病的前驱症状。