DEVELOPMENTAL REGULATION OF NEURON INSULIN-LIKE PEPTIDE

已知宫内生长迟缓会影响即刻和长期的 婴儿的足月神经系统结局。 然而，许多体液 参与生长控制和成功神经发育的因素 仍然不完全理解，无论是在因素的身份， 作用机制。 一个典型的例子是胰岛素， 反复显示，促进许多细胞的增殖和分化， 组织，包括神经元，并拥有改变的能力， 动物的进食（饱腹感）行为，从而改变整体生长 格局 在这种情况下，令人惊讶的是， 确切的性质，也不是“脑胰岛素”或胰岛素样肽的起源 (ILP)确立了习 实验室的初步数据， 与其他已发表的报告一起，表明脑胰岛素/ILP是 在神经元内局部合成，但在某些基本方面， 从胰腺激素。 此外，这些相同的初步数据也 提示脑胰岛素/ILP合成受 外源性胰岛素;这一观察结果将提供重要的见解 控制中枢神经系统中的胰岛素活性。 为了更全面地解决 这一点和几个同样基本的问题，我们建议：1）确定 兔脑发育中胰岛素/ILP合成的部位和模式 通过原位杂交，2）表征ILP的丰度和大小 不同胎龄和出生后即刻兔的mRNA 通过北方分析，3）确定外源性 胰岛素对稳态脑/神经元ILP mRNA丰度影响（北方） 4）建立神经元ILP和神经元ILP之间的同源性程度。 真正的胰腺胰岛素，和5）分离和表征神经元胰岛素， 通过筛选脑cDNA文库和DNA测序技术， 方法. 这些研究将有助于确定ILP的功能， 其序列元件在组织特异性表达和神经元 分化

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.