Growth hormone: an autocrine/paracrine in retinal function

这项建议是对生长激素（GH）分泌和作用的生理学研究的一个正在进行的计划的延伸。 虽然GH主要在垂体的生长激素细胞中合成，但申请人最近发现GH基因表达发生在许多垂体外组织中，包括GH作用部位的组织。 因此，生长激素可能有自分泌或旁分泌功能，除了它的内分泌作用。 在NSERC支持的最后一个周期中，早期鸡胚的神经视网膜被证明是GH产生和GH作用的位点。 此外，研究发现GH基因在视网膜神经节细胞（RGC）中的表达先于脑垂体中的表达，这为区分GH在视网膜发育中的局部和全身作用提供了一个独特的实验模型。 通过实验性阻断神经视网膜中的GH合成，申请人因此能够确定RGCs中GH基因的表达具有功能意义，并且在细胞凋亡的发育波期间参与RGC存活和参与RGC轴突生长。 在本申请中，将研究视网膜GH在早期视网膜发育期间另外参与细胞增殖、迁移和分化的可能性，以及其参与血管形成和RGC轴突与脑内视觉中心的突触的可能性。 GH也调节RGC的电生理信号传导的可能性也将被检查，视网膜GH对谷氨酸诱导的神经毒性具有神经保护作用的可能性也将被检查。 最后，将确定调节视网膜GH分泌的因素，并与调节垂体GH释放的因素进行比较。 这些研究将提供对视网膜生长激素分泌的进一步了解，它们可能揭示迄今未被怀疑的生长激素在视网膜功能中的自分泌或旁分泌作用。

This proposal is an extension of an on-going program of research on the physiology of growth hormone (GH) secretion and action. Although GH is mainly synthesized in somatotrophs cells of the pituitary gland, the applicant recently discovered that GH gene expression occurs in many extrapituitary tissues, including those that are sites of GH action. GH is thus likely to have autocrine or paracrine functions in addition to its endocrine roles. In the last cycle of NSERC support, the neural retina of the early chick embryo was shown to be both a site of GH production and GH action. Moreover, the expression of the GH gene in retinal ganglion cells (RGCs) was found to occur prior to that in the pituitary gland, providing a unique experimental model to differentiate between the local and systemic actions of GH in retinal development. By experimentally blocking GH synthesis in the neural retina, the applicant was thus able to establish that the expression of the GH gene in RGCs was of functional significance and involved in RGC survival during developmental waves of apoptosis and in RGC axon growth. In the current application the possibility that retinal GH is additionally involved in cell proliferation, migration and differentiation during early retinal development will be investigated, as will the possibility that it is involved in blood vessel formation and with the synapsing of the RGC axons to visual centers within the brain. The possibility that GH also modulates the electrophysiological signaling of RGCs will also be examined, as will the possibility that retinal GH is neuroprotective against glutamate-induced neurotoxicity. Finally, the factors regulating retinal GH secretion will be determined and compared with those regulating pituitary GH release. These studies will provide further understanding about retinal GH secretion they are likely to reveal hitherto unsuspected autocrine or paracrine roles of GH in retinal function.