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Phox2a/2b Function in the Mature Locus Coeruleus.

Phox2a/2b 在成熟蓝斑中的功能。

基本信息

批准号：
7391243
负责人：
MENG-YANG ZHU
金额：
$ 19.16万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7391243
关键词：
Adult Affect Age Aging Alzheimer&apos s Disease Anxiety Area Attention Birth Brain Characteristics Computer information processing Data Degenerative Disorder Dementia Development Dopamine Dopamine-beta-monooxygenase Elderly Elements Embryonic Development Functional disorder Gene Transfer Techniques Generations Genes Goals Hippocampus (Brain)Learning Lentivirus Vector Literature Maintenance Measures Mediating Memory Loss Mental Depression Messenger RNA Mixed Function Oxygenases Molecular Motor Nerve Degeneration Neurodegenerative Disorders Neurologic Neuronal Plasticity Neurons Other Finding Parkinson Disease Patients Personal Satisfaction Persons Play Process Proteins RNA Rattus Research Personnel Role Small Interfering RNA Symptoms System Testing Therapeutic Therapeutic Intervention Transgenic Organisms Work Yang age related aged aging brain base dentate gyrus homeodomain insight knock-down locus ceruleus structure neurogenesis neuron loss noradrenaline transporter noradrenergic olfactory bulb programs promoter transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dysfunction of the noradrenergic system and profound neuronal loss in the locus coeruleus (LC) of the brain is a common element of both aging and neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Although the deficiency in the central noradrenergic system has been recognized to play a critical role in the development and progression of aging, PD, and AD, the cause and mechanisms underlying the LC neuronal disturbance in these states are poorly understood. Phox2a and Phox2b are two homeodomain transcription factors. Exclusively expressed in noradrenergic neurons, these factors are determinants of the development of noradrenergic neurons. Our preliminary study demonstrated that the expression of Phox2a and Phox2b in the LC shows an age-associated reduction in rats, a process coincidently accompanied by the decreased expression of dopamine p-hydroxylase (DBH) and norepinephrine transporter (NET). As both DBH and NET are characteristic of the noradrenergic system, our preliminary data, together with other findings in the literature, indicated that there is a possible functional relevance between Phox2a/2b genes and the mature noradrenergic system. We hypothesize that Phox2a/2b genes play an important maintenance role for function of LC neurons in mature brains. This proposal will utilize the techniques of gene transfer and small interfering RNA (siRNA) to accomplish two specific aims: (1) To determine whether over-expression of Phox2a and Phox2b in the LC areas will boost the expression of DBH and NET per se and in terminal areas in adult rats; (2) To examine whether decreased expression, knock down, of endogenous Phox2a/2b genes in the LC will reduce the expression of DBH and NET in the LC and its terminal areas. Furthermore, the effect of these manipulations of the LC on the neuroplasticity in two terminal areas, the olfactory bulb and hippocampal dentate gyrus, will be investigated. This proposed work will provide new insights into causal interaction between Phox2 genes and the dysfunction of LC neurons in both aging and degenerative diseases. This information may greatly facilitate the development of meaningful, testable therapeutic intervention for aging, PD, and AD.

描述（由申请方提供）：去甲肾上腺素能系统功能障碍和大脑蓝斑（LC）中严重的神经元损失是衰老和神经退行性疾病（如帕金森病（PD）和阿尔茨海默病（AD））的常见因素。尽管中枢去甲肾上腺素能系统的缺陷已被公认在衰老、PD和AD的发展和进展中起关键作用，但对这些状态下LC神经元紊乱的原因和机制知之甚少。Phox 2a和Phox 2b是两种同源结构域转录因子。这些因子仅在去甲肾上腺素能神经元中表达，是去甲肾上腺素能神经元发育的决定因素。我们的初步研究表明，在LC中的Phox 2a和Phox 2b的表达表现出与年龄相关的减少，在大鼠，一个过程中巧合地伴随着多巴胺β-羟化酶（DBH）和去甲肾上腺素转运蛋白（NET）的表达减少。由于DBH和NET都是去甲肾上腺素能系统的特征，我们的初步数据以及文献中的其他发现表明，Phox 2a/2b基因和成熟的去甲肾上腺素能系统之间可能存在功能相关性。我们推测Phox 2a/2b基因在成熟脑中对LC神经元的功能起重要的维持作用。本研究拟利用基因转移技术和小干扰RNA（siRNA）技术，实现两个具体的目的：（1）确定Phox 2a和Phox 2b在LC区的过表达是否会促进DBH和NET本身和终末区的表达;（2）研究内源Phox 2a/2b基因在LC中的表达降低（敲低）是否会降低LC及其末端区域的DBH和NET的表达。此外，这些操作的LC上的神经可塑性在两个终端领域，嗅球和海马齿状回的影响，将进行调查。这项工作将为Phox 2基因与衰老和退行性疾病中LC神经元功能障碍之间的因果相互作用提供新的见解。这些信息可能会极大地促进有意义的，可测试的治疗干预老化，PD和AD的发展。