HYPOTHALAMIC RECONSTRUCTION USING NEURAL PRECURSOR CELLS

使用神经前体细胞进行下丘脑重建

• 批准号: 6229027
• 负责人: William J Schwartz
• 金额: $ 23.37万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6229027
• 关键词: arginine vasopressin; biomarker; circadian rhythms; diabetes insipidus; hypothalamus; in utero transplantation; laboratory mouse; nerve stem cell; neurotrophic factors; nonhuman therapy evaluation; paraventricular nucleus; stem cell transplantation; stem cells; suprachiasmatic nucleus; transfection

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.

描述：（逐字来自申请人的摘要） 自我更新，多能神经前体细胞提高了他们的希望， 可能的治疗效用，无论是通过细胞替代神经修复 或作为基因传递载体。移植是测试人类免疫系统的一个关键策略。 这种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脑区， 似乎分化成神经元和神经胶质细胞表型， 植入部位。细胞是否真的整合在一个 区域特定的、生理相关的时尚仍然没有答案。在 这个应用程序，我们将解决这个问题，利用独特的 两个下丘脑的解剖、生理、行为和分子遗传学 以前未被用作移植靶点的神经元系统 用于移植前体细胞。视交叉上核（SCN）是 调节昼夜运动节律的内源性时钟， 在时钟基因突变纯合子小鼠中被消除的行为。 室旁核（PVN）的大细胞分裂是 精氨酸加压素（AVP）分泌神经元调节水平衡， 在携带无效突变的尿崩症小鼠中丧失的功能 AVP基因。我们将移植一个原型神经前体细胞系 （C17.2;以及C17.2NT-3，一种过表达神经营养素-3的修饰克隆） 植入胚胎小鼠的端脑囊泡， 出生后解决三个问题：（A）植入的前体细胞是否假设 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 前体细胞对自然刺激的反应方式， SCN和PVN的神经元(C)植入的前体细胞 SCN和PVN恢复纯合时钟中缺陷行为， 显示昼夜节律紊乱和糖尿病的AVP缺陷突变小鼠 尿崩症，分别？这些问题的答案是初步的步骤 建立昼夜节律和下丘脑-神经垂体系统， 潜在的强大模型，用于分析结构和功能 植入前体细胞的可塑性。