MOLECULAR MECHANISMS OF NECROTICAL DEVLOPMENT

坏死发展的分子机制

• 批准号: 2260070
• 负责人: JANICE E BRUNSTROM
• 金额: $ 7.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2260070
• 关键词: cell cycle; cell membrane; cell migration; developmental neurobiology; extracellular matrix; fibronectins; genetically modified animals; glia; growth factor receptors; in situ hybridization; injection /infusion; integrins; intermolecular interaction; laboratory mouse; laboratory rat; ligands; neocortex; neurogenesis; neurons; neurotrophic factors; protein tyrosine kinase; receptor expression; tissue /cell culture

The objective of this proposal is to cultivate the abilities of the principal investigator as a developmental neurobiologist, teacher, and clinician, interested in neonatal neurology and early cortical development. Preparation of the principal investigator as a scientist and clinician will include: 1) intensive research training, focused on investigations of the molecular interactions involved in formation of the neocortex, 2) exposure to a rich academic and intellectual environment through participation in developmental neurobiology seminars and journal clubs, formal laboratory meetings, and clinical neurology seminars, and through recurring interactions with several established scientists and clinicians, 3) clinical exposure to patients with neurodevelopmental disorders in a setting that will allow enhancement of clinical skills and acquisition of the necessary tools to become an excellent teacher. The scientific research protocol will test the hypotheses that: 1) Fibronectin (via integrin-mediated binding) and the neuron-glia ligand, astrotactin, are vital participants in the migration of young neurons from their origin in the ventricular zone to their residence in the neocortex. 2) Developing cortical neurons display differential responses to neurotrophins that are both age-dependent and layer specific. 3) Cortical neurons express receptors specific for those neurotrophins to which they respond. 4) Cortical neurons are dependent on specific neurotrophins for proliferation, migration, maturation, and survival. To test these hypotheses, the principal investigator has developed an in vitro organotypic slice preparation that will allow perturbation of the neuron- glial and neuron-ECM interactions and quantitative assessment of the effects on migration. These slices will also be used to study the effects of neurotrophins in cortical development. Additionally, the principal investigator will acquire new skills, including in utero injection techniques to study the effects of neurotrophins on cortical development in vivo, and in situ hybridization techniques that will be used to analyze the developmental expression of tyrosine kinase receptors in specific populations of cortical neurons. The overall goal of this proposal is to advance the principal investigator's capabilities as a neuroscientist, clinician and teacher, so that she will be able to contribute effectively to the understanding of neocortical development. This understanding will ultimately advance the prevention and treatment of conditions such as mental retardation, learning disabilities and epilepsy, which are often due to underlying migrational defects, disorders of lamination and other aberrations of cortical development.

该提议的目的是培养 首席研究员作为发展性神经生物学家，教师和 临床医生，对新生儿神经病学和早期皮质感兴趣 发展。 为科学家和 临床医生将包括：1）强化研究培训，专注于 研究参与形成的分子相互作用 NeoCortex，2）接触丰富的学术和智力环境 通过参与发育神经生物学研讨会和杂志 俱乐部，正式的实验室会议和临床神经病学研讨会，以及 通过与几位知名科学家的反复互动和 临床医生，3）临床暴露于神经发育患者 在可以增强临床技能和的环境中的疾病 获取必要的工具以成为一名出色的老师。 科学研究方案将检验：1） 纤连蛋白（通过整联蛋白介导的结合）和神经元 - 胶质配体， 肌动蛋白是年轻神经元迁移的重要参与者 它们起源于室中新皮层的居住区。 2）发展皮质神经元显示出对 神经营养蛋白既依赖年龄又有特异性。 3）皮质 神经元表达特有的受体 回应。 4）皮质神经元取决于特定的神经营养蛋白 增殖，迁移，成熟和生存。 测试这些 假设，主要研究者已经开发了体外 器官型切片制剂将允许神经元的扰动 神经胶质和神经元ECM相互作用以及定量评估 对迁移的影响。 这些切片也将用于研究效果 皮质发育中的神经营养蛋白。 此外，校长 调查人员将获得新技能，包括在子宫注射中 研究神经营养蛋白对皮质发育的影响的技术 体内和原位杂交技术将用于分析 酪氨酸激酶受体在特定中的发育表达 皮质神经元的种群。 该提议的总体目标是 提高主要研究者作为神经科学家的能力， 临床医生和老师，以便她能够有效做出贡献 了解新皮质发展。 这种理解意志 最终提高了预防和治疗条件，例如 智力低下，学习障碍和癫痫病，通常是 由于基本的移民缺陷，层压障碍和其他 皮质发育的畸变。