DEVELOPMENTAL REGULATION OF NEURON INSULIN-LIKE PEPTIDE

众所周知，胎儿宫内发育迟缓会立即和长期影响 婴儿的足月神经结局。然而，许多幽默 与生长控制和成功的神经发育有关的因素 仍然不完全理解因素同一性和 作用机制。这方面的一个经典例子是胰岛素，它已经被 反复显示可促进多种细胞的增殖和分化 组织，包括神经元，并具有改变 动物的摄食(饱腹感)行为，从而改变整体生长 图案。在这种情况下，令人惊讶的是，无论是 精确的本质或“脑胰岛素”或胰岛素样肽的来源 (ILP)已经建立。取自本实验室的初步数据 与其他已发表的报告一起表明，脑内胰岛素/ILP是 在神经元内部局部合成，但可能在某些基本方面有所不同， 来自胰腺激素。此外，这些相同的初步数据也 提示大脑胰岛素/ILP合成受以下因素的调节 外源性胰岛素；这一观察将提供重要的见解 控制中枢神经系统中的胰岛素活性。要更全面地解决 这一点以及几个同样基本的问题，我们建议：1)确定 发育过程中兔脑内胰岛素/ILP合成的部位和模式 通过原位杂交，2)鉴定ILP的丰度和大小 胎兔不同发育阶段及出生后即刻的基因表达 发展用Northern分析，3)外源效应的确定 Northern研究胰岛素对稳态脑/神经元ILP基因表达的影响 分析，4)建立神经元ILP和ILP之间的同源性 真正的胰腺胰岛素，以及5)分离和鉴定神经细胞 白介素P和基因的筛选和DNA测序 方法：研究方法。 这些研究将有助于确定ILP的功能和 ITS序列元件在组织特异性表达和神经元中的作用 差异化。

Intrauterine growth retardation is known to affect the immediate and long term neurological outcome of the infant. However, many of the humoral factors involved in growth control and successful neurological development remain incompletely understood both in terms of factor identity and mechanism of action. A classic example of this is insulin which has been repeatedly shown to promote the proliferation and differentiation of many tissues, including neurons, and to possess the capacity of altering the feeding (satiety) behavior of animals, thereby modifying the overall growth pattern. Under these circumstances, it is surprising that neither the precise nature nor the origin of "brain insulin" or an insulin-like peptide (ILP) has been established. Preliminary data from this laboratory, taken together with other published reports, indicates that brain insulin/ILP is synthesized locally within neurons but may differ, in some fundamental way, from the pancreatic hormone. Moreover, these same preliminary data also suggest that brain insulin/ILP synthesis is subject to regulation by exogenous insulin; an observation which would offer significant insight into the control of insulin activity in the CNS. To more fully address this and several equally basic issues, we propose to: 1) Determine the sites and pattern of insulin/ILP synthesis in the developing rabbit brain by in situ hybridization, 2) Characterize the abundance and size of ILP mRNA at different stages of fetal and immediate postnatal rabbit development by Northern analysis, 3) Determine the effect of exogenous insulin on steady state brain/neuronal ILP mRNA abundance by Northern analysis, 4) Establish the degree of homology between neuronal ILP and authentic pancreatic insulin, and 5) Isolate and characterize the neuronal ILP and gene by screening a brain cDNA library and employing DNA sequencing methods. The studies will be instrumental in establishing the function of ILP and its sequence elements in tissue specific expression and neuronal differentiation.