Cell stress, development, and stimulant-induced behavior: Regulation by GSK3

细胞应激、发育和兴奋剂诱导的行为：GSK3 的调节

• 批准号: 8402898
• 负责人: MARJELO A MINES
• 金额: $ 1.86万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2014-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402898
• 关键词: Cell; stress; development; stimulant; induced

DESCRIPTION (provided by applicant): Glycogen synthase kinase-3 (GSK3) has widespread regulatory effects on cell signaling pathways and behavioral phenotypes associated with psychiatric diseases. Furthermore, GSK3 is a feasible therapeutic target because the GSK3 inhibitor lithium is already widely used as a treatment for bipolar disorder and many new small molecule selective GSK3 inhibitors are under development. Three specific aims will address important actions of GSK3 in cell signaling responses to stress, developmental changes in GSK3, and the role of GSK3 in behavioral responses to stimulants in young and adult mice. These goals will not only provide important information about these links between GSK3 and psychiatric illnesses, but will also provide the candidate with multidisciplinary training important for her career plans to establish an independent research laboratory focused on biomedical problems in biological psychiatry. Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded proteins, is associated with many diseases and activates both the UPR (unfolded protein response) and autophagy. These responses can allow cells to adapt and survive stress, or can lead to cell death, and inhibitors of GSK3 promote cell adaptation and reduce cell death, but the mechanisms for these regulatory actions are unclear. Specific Aim 1 will test the mechanisms by which GSK3 regulates the UPR and the balance between autophagy and apoptosis in ER stress. Many psychiatric diseases are initiated during development, and there has recently been a rapid increase in the prevalence of psychiatric diseases in young persons, particularly in attention-deficit/hyperactivity disorder (ADHD). However, it is unclear what predisposes young people during development to many major psychiatric diseases, such as ADHD, and if drugs administered during development have equivalent effects as in adults, where most testing was conducted. Of particular interest is the prevalent use of stimulants that activate dopaminergic signaling in the treatment of ADHD. Our laboratory has shown that 3 week old and 5 week old mice have much higher levels of GSK3 in the brain than adult mice, suggesting this may play a role in regulating developmental susceptibilities, and alter responses to dopaminergic stimulants that activate GSK3. Specific Aim 2 will test in mouse brain the developmental changes in GSK3 and its regulation by stimulants. Dopamine-mediated hyperactivity induced by amphetamine treatment is completely blocked by GSK3 inhibitors, signifying that activation of GSK3 following amphetamine is critical for this behavioral response. Specific Aim 3 will test in mice the role of GSK3 in mediating behavioral responses to stimulants during development compared with adult mice. Altogether, these goals will provide multidisciplinary training and will address topics critical for understanding the regulatory roles of GSK3 in cellular signaling in response to stress, during development, and in response to stimulants that are widely used in pre-adults. PUBLIC HEALTH RELEVANCE: Mental health disorders are the leading cause of disability in the United States, accounting for 25 percent of all years of life lost to disability and premature mortality (NIMH Strategic Plan, 2008). Progress in reducing the prevalence and severity of mental disorders requires coalescence of multiple strategies. Among these are understanding biochemical mechanisms that impair cellular functions, mechanisms controlling vulnerability, and behavioral outcomes of interventions, each of which is addressed by the three Specific Aims of this project.

描述（由申请人提供）：糖原合酶激酶-3（GSK3）对与精神病相关的细胞信号通路和行为表型具有广泛的调节作用。此外，GSK3是一个可行的治疗靶标，因为GSK3抑制剂锂已经被广泛用作双相情感障碍的治疗方法，许多新的小分子选择性GSK3抑制剂正在开发中。三个具体目标将解决GSK3在细胞信号反应，对压力，GSK3的发育变化以及GSK3在年轻小鼠和成年小鼠刺激剂中的作用中的重要作用。这些目标不仅将提供有关GSK3与精神病疾病之间这些联系的重要信息，而且还将为候选人提供对她职业生涯计划重要的多学科培训，以建立针对生物精神病学生物医学问题的独立研究实验室。 由错误折叠蛋白的积累产生的内质网（ER）应激与许多疾病有关，并激活UPR（未折叠的蛋白质反应）​​和自噬。这些反应可以使细胞适应和生存应激，或者可以导致细胞死亡，而GSK3的抑制剂促进细胞适应并减少细胞死亡，但是这些调节作用的机制尚不清楚。具体目标1将测试GSK3调节UPR和ER应力中自噬和凋亡之间的平衡的机制。在发育过程中启动了许多精神疾病，最近，年轻人的精神疾病患病率迅速增加，尤其是注意力缺陷/多动症疾病（ADHD）。但是，目前尚不清楚在发育过程中对许多主要的精神疾病（例如ADHD）的年轻人的容易患者，以及在发育过程中服用的药物是否具有类似的作用，就像在大多数测试中所做的一样。特别有趣的是，在ADHD治疗中激活多巴胺能信号传导的兴奋剂普遍使用。我们的实验室表明，大脑中的3周大和5周大的小鼠的GSK3水平高于成年小鼠，这表明这可能在调节发育敏感性中起作用，并改变对激活GSK3的多巴胺能兴奋剂的反应。特定的目标2将在小鼠大脑中测试GSK3的发育变化及其对兴奋剂的调节。 GSK3抑制剂完全阻断了苯丙胺治疗引起的多巴胺介导的多动症，这表明苯丙胺后GSK3的激活对于这种行为反应至关重要。与成年小鼠相比，特定的目标3将在小鼠中测试GSK3在发育过程中对兴奋剂的行为反应中的作用。 总的来说，这些目标将提供多学科的培训，并将解决对理解GSK3在响应压力，发育过程中以及响应于在成年前广泛使用的刺激物中的细胞信号传导调节作用至关重要的主题。 公共卫生相关性：心理健康障碍是美国残疾的主要原因，占残疾和早死亡的所有年生的25％（NIMH战略计划，2008年）。减少精神障碍的患病率和严重程度的进展需要多种策略的合并。其中包括了解损害细胞功能的生化机制，控制脆弱性的机制以及干预措施的行为结果，每种都由该项目的三个特定目标解决。