Glucocorticoid and Stress Induced Cerebellar Neural Progenitor Cell Apoptosis

糖皮质激素和应激诱导的小脑神经祖细胞凋亡

• 批准号: 7904024
• 负责人: KEVIN K NOGUCHI
• 金额: $ 14.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-31 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904024
• 关键词: Acute; Affective; Apoptosis; Apoptotic; Area; Behavior; Behavioral; Birth; Brain; Brain region; Cell Count; Cerebellar Diseases; Cerebellum; Cessation of life; Clinical; Clinical Research; Cognitive; Cognitive deficits; Control Groups; Corticosterone; Development; Disease; Drug Kinetics; Electron Microscopy; Exposure to; Fetus; Figs - dietary; Functional disorder; Genetic Recombination; Glucocorticoid Receptor; Glucocorticoids; Healthcare; Hormones; Human; Immunohistochemistry; Infant; Injection of therapeutic agent; Knock-out; Knockout Mice; Lead; Learning; Link; Lithium; Long-Term Effects; Maintenance; Measures; Medical; Mus; Neonatal; Nervous system structure; Neurodevelopmental Deficit; Neurons; Nuclear Pore Complex; Occupations; Patients; Pattern; Perinatal; Pharmaceutical Preparations; Play; Population; Pregnancy; Preventive; Production; Radioimmunoassay; Receptor Gene; Research; Research Personnel; Research Training; Rest; Rodent; Role; Rosa; Saline; Signal Transduction; Stress; Structure; System; Techniques; Testing; Toxic effect; Training; Transgenic Animals; Viral Vector; Virus Diseases; Yang; brain volume; career development; cerebellar lesion; fetal; granule cell; insight; interest; neonatal exposure; neonate; nerve stem cell; neurodevelopment; neurogenesis; neuroimaging; neuron apoptosis; novel; perinatal health; postnatal; premature; prevent; progenitor; programs; public health relevance; response; stem; synaptogenesis

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.

描述（由申请人提供）：有大量证据表明，围产期糖皮质激素（GC）暴露，无论是药物的给药还是在极端围产压力的时期，可以产生神经发育缺陷，从而导致永久性神经精神疾病。在我们的初步结果中，我们发现GC的急性注射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祖细胞（NFC）凋亡变性的模式。因此，描述这种毒性的基本机制有可能为围产期医疗保健和Neustevepment的基本机制提供重要信息。尽管传统上，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起着关键作用。因此，这项研究还可能表明GC诱导的小脑功能障碍在A中的作用 各种神经精神症状。与这个想法一致，与盐水对照组相比，已经发现暴露于GC的过早出生的婴儿会出现认知和神经运动缺陷。同样重要的是，暴露于围产期应激与认知和情感功能障碍有关，并与多种神经心理局势有关。在AIM 1中，申请人将测试潜在的Safener Drug锂，以防止GC诱导的NPC凋亡及其在小脑中的长期影响。在AIM 2中，申请人将确定与皮质酮释放增加相关的围产期应激范式是否会急性地产生小脑NPC的凋亡，并在小脑颗粒细胞中长期减少。最后，在AIM 3中，申请人将利用CRE/LOX重组系统在小脑NPC中有选择性地敲除GC受体，以确定其在这种毒性和小脑发育中的作用。在进行拟议的研究计划时，申请人将在对其职业发展至关重要的几个领域进行培训，包括免疫组织化学，药代动力学，电子显微镜，立体学，使用基因敲除小鼠和有条件的基因敲除小鼠，放射免疫分子以及病毒载体维护和使用。 公共卫生相关性：目前，大量的胎儿/新生儿暴露于GCS围产期医疗或与围产期应激相关的内源性释放期间。已知这两种情况都会产生永久性的行为缺陷，但对这种情况的发生知之甚少。因此，这项研究可能会提供有关接触GC对围产期健康的影响的关键见解。