Phox2a/2b Function in the Mature Locus Coeruleus.

Phox2a/2b 在成熟蓝斑中的功能。

• 批准号: 7208410
• 负责人: MENG-YANG ZHU
• 金额: $ 15.97万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208410
• 关键词: Adult; Affect; Age; Aging; Alzheimer' 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

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（由申请人提供）：甲肾上腺素能系统的功能障碍和大脑基因座（LC）的严重神经元丧失是衰老和神经退行性疾病（例如帕金森氏病（PD）和阿尔茨海默氏病（AD））的共同元素。尽管已确认中央甲肾上腺素能系统的缺乏在衰老，PD和AD的发展和进展中起着至关重要的作用，但在这些状态下LC神经元障碍的原因和机制知之甚少。 PHOX2A和PHOX2B是两个同源域转录因子。这些因素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展的决定因素。我们的初步研究表明，LC中PHOX2A和PHOX2B的表达表明大鼠与年龄相关的减少，这一过程恰好伴随着多巴胺P-羟化酶（DBH）和去甲肾上腺素转运蛋白的表达降低。由于DBH和NET都是去甲肾上腺素能系统的特征，因此我们的初步数据以及文献中的其他发现表明，PHOX2A/2B基因与成熟的去甲肾上腺素能系统之间存在可能的功能相关性。我们假设PHOX2A/2B基因在成熟大脑中LC神经元的功能起着重要的维护作用。该提案将利用基因转移的技术和小型干扰RNA（siRNA）来实现两个具体目标：（1）确定LC区域中Phox2a和Phox2b的过表达是否会促进成年大鼠中DBH和净本质和末端区域的表达； （2）检查LC中内源性PHOX2A/2B基因的表达降低，是否会降低LC及其末端区域中DBH和NET的表达。此外，将研究这些操纵LC对两个末端区域神经可塑性的影响，即嗅球和海马齿状回。这项拟议的工作将为衰老和退化性疾病中PHOX2基因与LC神经元功能障碍之间的因果相互作用提供新的见解。这些信息可能极大地促进了对衰老，PD和AD的有意义的，可测试的治疗干预措施的开发。