HORMONE ACTION IN THE CENTRAL NERVOUS SYSTEM

中枢神经系统中的激素作用

• 批准号: 2150967
• 负责人: ALAN P FARWELL
• 金额: $ 10万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2150967
• 关键词: brain; cell migration; developmental neurobiology; hormone regulation /control mechanism; thyroid hormones

This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. The absence of thyroid hormone during the period of active neurogenesis is accompanied by multiple morphological alterations in the brain that result in irreversible mental retardation (cretinism). These severe morphological alterations in the cretinous brain can be attributed to deficits in neuronal migration and axonal projection which lead to attenuation of neural circuits. The goal of this proposal is the characterization of mechanism(s) by which thyroid hormone can influence neuronal migration in the developing brain by regulating the ability of brain cells to interact with their extracellular environment. Previous work in our laboratory has shown that thyroid hormone regulates polymerization of the actin cytoskeleton in cultured astrocytes. Further studies have shown that modulation of the microfilament organization by thyroid hormone alters the ability of the cell to form attachments to laminin, a major component of the extracellular matrix (ECM) in the developing brain that provides key guidance cues to the elongating neurite during migration. MY working hypothesis is that thyroid hormone regulates interactions between the microfilaments, transmembrane receptors known as integrins and the ECM in both astrocytes and neurons. In the hypothyroid astrocyte, this would result in disorganized patterning of ECM proteins on the cell surface that would disrupt spacial cues essential to guide the migrating neurite to its target destination. In the neurite, altered cytoskeletal-integrin interactions in the absence of thyroid hormone would interfere with the ability of the neurite to transduce these spatial cues. Indeed, microinjection of an antibody to the integrin that recognizes both laminin and fibronectin, another component of the brain ECM, blocks neural crest cell migration in chick embryos. The first part of this proposal will characterize the effect of thyroid hormone on the synthesis, secretion, and distribution of laminin and fibronectin by astrocytes, both in vivo and in vitro. The second part will examine the effect of altered integrin-ECM interactions on neurite outgrowth. The final section will examine how thyroid hormone can regulate ECM-derived cues by altering integrin-mediated activation of intracellular signaling pathways. These studies will provide a possible mechanism for the profound effects of thyroid hormone on the developing brain. In addition, these studies will begin to address some of the fundamental questions of how cells interact, respond and adapt to their environment.

这是一个香农奖提供部分支持的研究 项目不属于指定的研究所的资金范围，但 都处于优秀的边缘。 香农奖旨在 提供支持，以测试该方法的可行性;进一步发展 测试和完善研究技术;进行二次分析 可用的数据集;或进行离散项目， PI的研究能力或为已经存在的 有价值的申请。 下面的摘要摘自原文 主要研究者提交的文件。 神经发生活跃期甲状腺激素缺乏 伴随着大脑的多种形态学改变， 导致不可逆转的智力迟钝（克汀病）。 这些严重 克汀病脑的形态学改变可归因于 神经元迁移和轴突投射的缺陷导致 神经回路的衰减 该提案的目标是 甲状腺激素可影响的机制表征 神经元迁移在发育中的大脑通过调节的能力， 脑细胞与细胞外环境相互作用。 先前 我们实验室的工作表明甲状腺激素调节 在培养的星形胶质细胞中肌动蛋白细胞骨架的聚合。 进一步 研究表明，通过调节微丝组织， 甲状腺激素改变细胞形成附着物的能力， 层粘连蛋白，细胞外基质（ECM）的主要成分， 发育中的大脑提供了关键的指导线索， 迁移过程中的神经突。 我的假设是甲状腺激素 调节微丝之间的相互作用，跨膜 在星形胶质细胞和神经元中的整合素和ECM受体。 在甲状腺功能减退的星形胶质细胞中， 细胞表面ECM蛋白的图案化， 引导迁移的神经突到达其目标目的地的关键线索。 在神经突中，在缺乏细胞因子的情况下， 甲状腺激素会干扰神经突 注意这些空间线索。 事实上，显微注射抗体， 整合素识别层粘连蛋白和纤连蛋白，另一种 脑细胞外基质的一种成分，阻断鸡的神经嵴细胞迁移 胚胎 本提案的第一部分将描述 甲状腺激素的合成，分泌和分布 层粘连蛋白和纤连蛋白的星形胶质细胞，在体内和体外。 的 第二部分将研究改变整合素-ECM相互作用的影响 神经突生长 最后一节将研究甲状腺激素 可以通过改变整合素介导的激活来调节ECM来源的信号 细胞内信号传导途径。 这些研究将提供一个 甲状腺激素对甲状腺功能影响的可能机制 大脑发育 此外，这些研究将开始解决一些 细胞如何相互作用，反应和适应的基本问题 他们的环境。