Multi functional studies of candidate dyslexia susceptibility genes in the rat

大鼠候选阅读障碍易感基因的多功能研究

• 批准号: 8914759
• 负责人: ALBERT Mark GALABURDA
• 金额: $ 17.78万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914759
• 关键词: Anatomy; Animal Model; Architecture; Auditory; Behavior; Behavior Therapy; Behavioral; Brain; Cell Adhesion; Cells; Defect; Development; Developmental reading disorder; Dyslexia; Early Diagnosis; Electroporation; Genes; Genetic Variation; Homologous Gene; Human; Laboratories; Learning; Learning Disabilities; Light; Methods; Modeling; Molecular; Morphology; Movement; Neurons; Nuclear; Pathway interactions; Procedures; Process; Rattus; Structure; Susceptibility Gene; Ventricular; base; computerized data processing; developmental neurobiology; developmental plasticity; genetic manipulation; improved; in utero; interest; migration; morphometry; overexpression; programs; small hairpin RNA

The proposed Program Project is to study a unique rat model of developmental learning disability that uses methods of developmental neurobiology, structural anatomy, and behavior to analyze the functions of three candidate dyslexia susceptibility genes (CDSGs). Neuropathologic studies in human dyslexic brains and previous animal models have underscored the importance of focal neuronal migration defects and developmental plasticity for some of the dyslexic deficits. The discovery of CDSGs challenges us to analyze the effects of this genetic variation on brain development, structure, and behavior with respect to learning disability. Using an in utero electroporation method developed in our laboratories, we will transfect into young neurons in the ventricular zone short hairpin RNAs or over-expression constructs targeted against homologs in the rat of CDSG Dyxicl, Kiaa0319, or Dcdc2. We have already seen that this procedure leads to abnormal neuronal migration, alters neuronal morphology, and causes secondary effects in untouched neighboring neurons, thus producing a picture reminiscent of dyslexic brains. Interesting behavioral alterations are also seen. Project I (J.J. LoTurco, PI) will analyze Dyxicl's interaction with genes with known molecular pathways involved in process extension, nuclear movement, and cell adhesion, the domains on the Dyxicl critical to function. Project II (A.M. Galaburda, PI) will characterize anatomic changes (cortical architecture, cell identity, morphology, and connectivity) associated with knockdown or overexpression of CDSGs. Project III (H. Fitch, PI) will uncover behavioral consequences of CDSG disruption (auditory processing and learning), and will attempt to ameliorate the effects of these genetic manipulations by behavioral interventions. The three interactive projects will be supported by an Administrative Core, an In Utero Electroporation Core, and a Neurohistology, Morphometry, and Data Processing Core. A better understanding of the functions of CDSGs will shed a broader light on mechanisms of normal brain development and on the abnormalities seen in developmental dyslexia, but also offering the possibility of earlier detection, biologically-based subtyping, and improved treatment.

拟议的计划项目是研究一个独特的大鼠模型的发展性学习障碍，使用 发育神经生物学，结构解剖学和行为学的方法来分析三个功能 候选阅读障碍易感基因（CDSGs）。人类睡眠障碍脑的神经病理学研究 先前的动物模型强调了局灶性神经元迁移缺陷的重要性， 某些睡眠障碍缺陷的发育可塑性。CDSGs的发现挑战我们分析 这种遗传变异对大脑发育、结构和学习行为的影响 残疾。使用我们实验室开发的子宫内电穿孔方法，我们将插入 心室区中的年轻神经元短发夹RNA或过表达构建体靶向 大鼠中的CDSG Dyxicl、Kiaa0319或Dcdc2的同源物。我们已经看到，这个过程导致 异常的神经元迁移，改变神经元形态，并在未触及的情况下引起继发性影响。 邻近的神经元，从而产生一幅让人联想到睡眠障碍大脑的图像。有趣的行为 也可以看到变化。项目I（J.J. LoTurco，PI）将分析Dyxicl与基因的相互作用， 已知的分子途径涉及过程延伸、核运动和细胞粘附， Dyxicl上对功能至关重要的区域。项目II（A.M. Galaburda，PI）将描述解剖结构 与基因敲除相关的变化（皮质结构、细胞特性、形态学和连接性），或 CDSG的过度表达。项目三（H.惠誉，PI）将揭示CDSG的行为后果 干扰（听觉处理和学习），并将试图改善这些遗传因素的影响， 通过行为干预进行操纵。这三个互动项目将得到一个 管理核心，子宫内膜电穿孔核心，以及神经组织学，形态测量学和数据 处理核心。更好地理解CDSG的功能将有助于更广泛地了解 正常大脑发育的机制和发育性阅读障碍中的异常，但 还提供了早期检测、基于生物学的亚型分型和改善治疗的可能性。

项目成果

Deficits in learning and memory in mice with a mutation of the candidate dyslexia susceptibility gene Dyx1c1.

候选阅读障碍易感基因 Dyx1c1 发生突变的小鼠的学习和记忆缺陷。

• DOI: 10.1016/j.bandl.2015.04.008
• 发表时间: 2017
• 期刊: Brain and language
• 影响因子: 2.5
• 作者: Rendall,AmandaR;Tarkar,Aarti;Contreras-Mora,HectorM;LoTurco,JosephJ;Fitch,RHolly
• 通讯作者: Fitch,RHolly

Knockdown of the candidate dyslexia susceptibility gene homolog dyx1c1 in rodents: effects on auditory processing, visual attention, and cortical and thalamic anatomy.

• DOI: 10.1159/000348431
• 发表时间: 2013
• 期刊: Developmental neuroscience
• 影响因子: 2.9
• 作者: Szalkowski CE;Booker AB;Truong DT;Threlkeld SW;Rosen GD;Fitch RH
• 通讯作者: Fitch RH

Learning delays in a mouse model of Autism Spectrum Disorder.

• DOI: 10.1016/j.bbr.2016.02.006
• 发表时间: 2016-04-15
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Rendall AR;Truong DT;Fitch RH
• 通讯作者: Fitch RH

Auditory processing enhancements in the TS2-neo mouse model of Timothy Syndrome, a rare genetic disorder associated with autism spectrum disorders.

• DOI: 10.1007/s41252-017-0029-1
• 发表时间: 2017-09
• 期刊: Advances in neurodevelopmental disorders
• 作者: Rendall AR;Ford AL;Perrino PA;Holly Fitch R
• 通讯作者: Holly Fitch R

Position of neocortical neurons transfected at different gestational ages with shRNA targeted against candidate dyslexia susceptibility genes.

• DOI: 10.1371/journal.pone.0065179
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Adler WT;Platt MP;Mehlhorn AJ;Haight JL;Currier TA;Etchegaray MA;Galaburda AM;Rosen GD
• 通讯作者: Rosen GD