HORMONE ACTION IN THE CENTRAL NERVOUS SYSTEM

这是香农奖，为这项研究提供部分支持

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.