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: 8467723
• 负责人: ALBERT Mark GALABURDA
• 金额: $ 94.36万
• 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/8467723
• 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种独特的发育性学习障碍大鼠模型，该模型使用 发育神经生物学、结构解剖学和行为学的方法来分析三者的功能 候选阅读障碍易感基因（CDSG）。人类阅读障碍大脑的神经病理学研究 以前的动物模型强调了局灶性神经元迁移缺陷的重要性， 某些阅读障碍缺陷的发育可塑性。 CDSG 的发现挑战我们去分析 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，我们将转染 心室区的年轻神经元短发夹 RNA 或针对的过表达构建体 大鼠中 CDSG Dyxicl、Kiaa0319 或 Dcdc2 的同源物。我们已经看到这个过程导致 导致神经元迁移异常，改变神经元形态，并对未受影响的神经元造成二次影响 邻近的神经元，从而产生让人想起阅读障碍大脑的图像。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 已知的参与过程延伸、核运动和细胞粘附的分子途径， Dyxicl 上对功能至关重要的结构域。项目 II（A.M. Galaburda，PI）将描述解剖学特征 与敲低或相关的变化（皮质结构、细胞身份、形态和连接性） CDSG 的过度表达。项目 III（H. Fitch，PI）将揭示 CDSG 的行为后果 破坏（听觉处理和学习），并将尝试改善这些遗传的影响 通过行为干预进行操纵。这三个互动项目将得到 管理核心、子宫内电穿孔核心以及神经组织学、形态测量和数据 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以及发育性阅读障碍中所见的异常，但是 还提供了早期检测、基于生物学的亚型和改进治疗的可能性。