HYPOTHALAMIC RECONSTRUCTION USING NEURAL PRECURSOR CELLS

描述：(逐字摘自申请人的摘要)发现 自我更新的多潜能神经前体细胞为他们的 可能的治疗作用，无论是通过细胞替代进行神经修复 或者作为基因输送工具。移植是测试 这些细胞的分化能力和功能活性；当前体 从一个脑区获得的细胞被移植到另一个区域，他们 似乎分化为神经元和神经胶质表型适合于 植入地点。无论细胞是否真的整合在一个 特定地区的、与生理相关的时尚仍未得到回应。在……里面 这个应用程序，我们将通过利用独特的 两个下丘脑的解剖、生理、行为和分子遗传学 以前没有被用作植入靶点的神经系统 用于移植的前体细胞。视交叉上核(SCN)是 在调节昼夜运动节律性的内源性时钟中， 在时钟基因突变纯合子小鼠中被取消的行为。 室旁核(PVN)的大细胞分裂是 精氨酸加压素(AVP)分泌的神经元调节水平衡，a 携带零突变的尿崩症小鼠丧失的功能 血管紧张素转换酶基因。我们将移植一个原型神经前体细胞系 (C17.2；以及C17.2NT-3，一个高表达神经营养素-3的修饰克隆) 进入胚胎小鼠的端脑小泡，然后检查小鼠 以解决三个问题：(A)植入的前体细胞是否假定 形态、肽能表型和传出投射 SCN和PVN固有神经元的特征？(B)可嫁接 前体细胞以模拟反应的方式对自然刺激做出反应 SCN和PVN的固有神经元？(C)将移植的前体细胞植入 SCN和PVN恢复纯合子时钟和 表现出昼夜节律性心律失常和糖尿病的AVP缺陷突变小鼠 分别是尿崩症？这些问题的答案只是第一步 建立昼夜节律和下丘脑-神经垂体系统 潜在强大的模型，用于分析结构和功能 植入的前体细胞的可塑性。

DESCRIPTION: (Verbatim from the Applicant's Abstract) The discovery of self-renewing, multipotent neural precursor cells has raised hopes for their possible therapeutic utility, either for neural repair through cell replacement or as gene-delivery vehicles. Transplantation is a key strategy for testing the differentiation capacity and functional activity of such cells; when precursor cells obtained from one brain region are transplanted to another region, they appear to differentiate into neuronal and glial phenotypes appropriate to the implantation site. Whether the cells actually integrate in a regionally-specific, physiologically-relevant fashion remains unanswered. In this application, we will address this question by capitalizing on the unique anatomy, physiology, behavior, and molecular genetics of two hypothalamic neuronal systems that have not been previously exploited as engraftment targets for transplanted precursor cells. The suprachiasmatic nucleus (SCN) is the site of an endogenous clock that regulates circadian locomotor rhythmicity, a behavior that is abolished in mice homozygous for a mutation of the clock gene. The magnocellular division of the paraventricular nucleus (PVN) is the site of arginine vasopressin (AVP)-secreting neurons that regulate water balance, a function that is lost in mice with diabetes insipidus bearing a null mutation of the AVP gene. We will transplant a prototypic neural precursor cell line (C17.2; as well as C17.2NT-3, a modified clone overexpressing neurotrophin-3) into the telencephalic vesicle of embryonic mice and then examine the mice postnatally to address three questions: (A) Do engrafted precursor cells assume the morphologies, peptidergic phenotypes, and efferent projections characteristic of neurons indigenous to the SCN and PVN? (B) Can engrafted precursor cells respond to natural stimuli in ways that emulated the response of neurons indigenous to the SCN and PVN? (C) Will engrafted precursor cells in the SCN and PVN restore defective behaviors in homozygous clock and AVP-deficient mutant mice exhibiting circadian arrhythmicity and diabetes insipidus, respectively? The answers to these questions are initial steps towards establishing the circadian and hypothalamo-neurohypophyseal systems as potentially powerful models for analyzing the structural and functional plasticity of implanted precursor cells.