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: 8109368
• 负责人: KEVIN K NOGUCHI
• 金额: $ 14.72万
• 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/8109368
• 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; Functional disorder; Genetic Recombination; Glucocorticoid Receptor; Glucocorticoids; Health; 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; 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; 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，无论是给药还是在围产期极度应激期间，围产期糖皮质激素（GC）暴露都会导致神经发育缺陷，从而导致永久性神经精神障碍。在我们的初步结果中，我们发现急性注射GC和暴露于新生儿应激都会在发育中的啮齿动物小脑中产生相同模式的神经祖细胞（NFC）凋亡变性。因此，描述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。虽然小脑传统上与神经运动功能有关，但最近的研究证实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 各种神经精神疾病。与这一观点一致的是，与盐水对照组相比，暴露于GC的早产儿被发现会出现认知和神经运动缺陷。同样重要的是，围产期压力与认知和情感功能障碍有关，并与多种神经精神疾病有关。在目标 1 中，申请人将测试潜在的安全剂药物锂，以了解其防止 GC 诱导的 NPC 细胞凋亡的能力及其对小脑的长期影响。在目标 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例是否可以在小脑 NPC 中急剧产生细胞凋亡，并在小脑颗粒细胞中产生长期减少。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。在进行拟议的研究计划时，申请人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敲除小鼠的使用、放射免疫测定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/新生儿在围产期医疗或与围产期应激相关的内源性释放过程中接触GC。众所周知，这两种情况都会产生永久性的行为缺陷，但人们对其如何发生知之甚少。因此，这项研究可能为了解GCs暴露对围产期健康的影响提供重要见解。