Glucocorticoid and Stress Induced Cerebellar Neural Progenitor Cell Apoptosis

描述(由申请人提供)：有相当多的证据表明，围产期接触糖皮质激素(GC)，无论是药物管理还是在围产期极端应激期间，都会导致神经发育缺陷，导致永久性神经心理障碍。在我们的初步结果中，我们发现，急性注射GCs和暴露于新生儿应激都可以在发育中的啮齿动物小脑中产生相同的神经前体细胞(NFC)凋亡变性模式。因此，阐明这种毒性的潜在机制有可能为围产期保健和神经发育的基本机制提供重要信息。虽然传统上小脑与神经运动功能有关，但最近的研究表明，它在认知和情感行为中发挥着关键作用。因此，这项研究也可能表明GC诱导的小脑功能障碍在 各种神经心理状况。与这一观点一致，与生理盐水对照组相比，暴露于GCs的早产儿被发现出现认知和神经运动障碍。同样重要的是，围产期应激暴露与认知和情感功能障碍有关，并与各种神经心理疾病有关。在目标1中，申请人将测试潜在的更安全的药物锂的能力，以防止GC诱导的鼻咽癌细胞凋亡，以及它对小脑的长期影响。在目标2中，申请者将确定与皮质酮释放增加相关的围产期应激范例是否可以迅速导致小脑NPC细胞凋亡，并导致小脑颗粒细胞长期减少。最后，在目标3中，申请人将利用Cre/lox重组系统选择性地敲除小脑NPC中的GC受体，以确定它们在这种毒性和小脑发育中的作用。在执行拟议的研究计划时，申请者将接受对其职业发展至关重要的几个领域的培训，包括免疫组织化学、药代动力学、电子显微镜、体视学、基因敲除小鼠和条件基因敲除小鼠的使用、放射免疫分析以及病毒载体的维护和使用。公共卫生相关性：目前，大量胎儿/新生儿因围产期医疗或在与围产期应激相关的内源性释放期间暴露于GCs。众所周知，这两种情况都会产生永久性的行为缺陷，但人们对这种情况是如何发生的知之甚少。因此，这项研究可能对暴露于GCs对围产期健康的影响提供关键的见解。

DESCRIPTION (provided by applicant): There is considerable evidence that perinatal glucocorticoid (GC) exposure, either from the administration of drugs or during periods of extreme perinatal stress, can produce neurodevelopmental deficits leading to permanent neuropsychlatric disorders. In our preliminary results, we have found that acute injections of GCs and exposure to neonatal stress can both produce an identical pattern of neural progenitor cell (NFC) apoptotic degeneration in the developing rodent cerebellum. Therefore, delineating the underlying mechanisms for this toxicity has the potential to provide important information for perinatal healthcare and basic mechanisms of neuredevelopment. While the cerebellum has traditionally been associated with neuromotor function, recent research has established that it plays a critical role in cognitive and affective behaviors. Therefore, this research may also suggest a role for GC induced cerebellar dysfunction in a variety of neuropsychlatric conditions. Consistent with this idea, prematurely born infants exposed to GCs have been found to develop cognitive and neuromotor deficits when compared to a saline control group. Of equal importance, exposure to perinatal stress has been associated with cognitive and affective dysfunction and has been implicated in a variety of neuropsychlatric conditions. In Aim 1, the applicant will test the potential safener drug lithium for its ability to protect against GC induced NPC apoptosis and its long term effects in the cerebellum. In Aim 2, the applicant will determine whether a perinatal stress paradigm associated with increased corticosterone release can produce apoptosis in cerebellar NPCs acutely and produce long term reductions in cerebellar granule cells. Finally, in Aim 3, the applicant will make use of the Cre/lox recombination system to selectively knockout GC receptors in the NPCs of the cerebellum in order to determine their role in this toxicity and cerebellar development. While conducting the proposed research plan the applicant will become trained in several areas critical for his career development including immunohistochemistry, pharmacokinetics, electron microscopy, stereology, the use of both knockout mice and conditional knockout mice, radioimmunoassay, and viral vector maintenance and use. PUBLIC HEALTH RELEVANCE: Currently, a large number of fetuses/neonates are exposed to GCs for either perinatal medical treatment or during the endogenous release associated with perinatal stress. Both of these conditions are known to produce permanent behavioral deficits yet little is known about how this occurs. Therefore, this research may provide key insights on the effects of exposure to GCs on perinatal health.