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: 8262093
• 负责人: MARJELO A MINES
• 金额: $ 5.39万
• 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 2013-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262093
• 关键词: Accounting; Address; Adolescent; Adult; Alanine; Amphetamines; Apoptosis; Apoptotic; Attention deficit hyperactivity disorder; Autophagocytosis; Behavior; Behavior assessment; Behavioral; Biochemical; Biological Psychiatry; Bipolar Disorder; Brain; Brain region; Cell Death; Cell physiology; Cells; Cellular Stress; Cerebral cortex; Cognition; Development; Disease; Dopamine; Equilibrium; Etiology; Figs - dietary; Glycogen Synthase Kinase 3; Goals; Hyperactive behavior; Intervention; Laboratories; Laboratory Research; Lead; Link; Lithium; Measures; Mediating; Mental disorders; Methylphenidate; Molecular; Mood Disorders; Mood stabilizers; Moods; Mus; Mutate; Mutation; National Institute of Mental Health; Neurodegenerative Disorders; Outcome; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phosphorylation; Physiological; Play; Predisposition; Premature Mortality; Prevalence; Protein Biosynthesis; Protein Isoforms; Proteins; Recovery; Regulation; Role; Schizophrenia; Serine; Severities; Signal Pathway; Signal Transduction; Strategic Planning; Stress; Testing; Therapeutic Intervention; Training; United States; burden of illness; career; cell growth regulation; cell type; disability; endoplasmic reticulum stress; inhibitor/antagonist; interest; multidisciplinary; mutant; promoter; protein misfolding; public health relevance; response; small molecule; therapeutic target; young adult

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）：糖原合成酶激酶-3（GSK 3）对与精神疾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，GSK 3是一个可行的治疗靶点，因为GSK 3抑制剂锂已经被广泛用作双相情感障碍的治疗，并且许多新的小分子选择性GSK 3抑制剂正在开发中。三个具体的目标将解决的重要行动，GSK 3在细胞信号传导反应的压力，GSK 3的发展变化，和GSK 3的作用，在行为反应的刺激在年轻和成年小鼠。这些目标不仅将提供有关GSK 3和精神疾病之间联系的重要信息，而且还将为候选人提供多学科培训，这对她的职业计划至关重要，以建立一个专注于生物精神病学生物医学问题的独立研究实验室。 内质网（ER）应激，由错误折叠蛋白质的积累引起，与许多疾病相关，并激活UPR（未折叠蛋白质反应）和自噬。这些反应可以使细胞适应并在压力下存活，或者可以导致细胞死亡，而GSK 3抑制剂促进细胞适应并减少细胞死亡，但这些调节作用的机制尚不清楚。具体目标1将测试GSK 3调节UPR以及ER应激中自噬和凋亡之间平衡的机制。许多精神疾病是在发育期间开始的，最近青年人精神疾病的流行率迅速增加，特别是注意力缺陷/多动症。然而，目前尚不清楚是什么使年轻人在发育过程中容易患上许多主要的精神疾病，如多动症，以及在发育过程中给予的药物是否具有与成人相同的效果，大多数测试都是在成人中进行的。特别令人感兴趣的是在ADHD的治疗中激活多巴胺能信号传导的兴奋剂的普遍使用。我们的实验室已经表明，3周龄和5周龄的小鼠大脑中的GSK 3水平比成年小鼠高得多，这表明这可能在调节发育能力方面发挥作用，并改变对激活GSK 3的多巴胺能兴奋剂的反应。Specific Aim 2将在小鼠大脑中测试GSK 3的发育变化及其受兴奋剂的调节。苯丙胺治疗诱导的多巴胺介导的多动症被GSK 3抑制剂完全阻断，这表明苯丙胺后GSK 3的激活对这种行为反应至关重要。具体目标3将在小鼠中测试与成年小鼠相比，GSK 3在发育期间介导对刺激物的行为反应中的作用。 总之，这些目标将提供多学科的培训，并将解决关键的主题，以了解GSK 3在细胞信号传导中的调节作用，以应对压力，在发展过程中，并在响应兴奋剂，广泛用于成年前。 公共卫生相关性：精神健康障碍是美国残疾的主要原因，占因残疾和过早死亡而损失的所有生命年数的25%（NIMH战略计划，2008年）。要在减少精神障碍的流行率和严重程度方面取得进展，就需要将多种战略结合起来。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，每一个都由本项目的三个具体目标解决。

项目成果

Glycogen synthase kinase-3 levels and phosphorylation undergo large fluctuations in mouse brain during development.

• DOI: 10.1111/bdi.12023
• 发表时间: 2012-12
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: Beurel E;Mines MA;Song L;Jope RS
• 通讯作者: Jope RS

Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice.

• DOI: 10.1016/j.cellsig.2012.03.001
• 发表时间: 2012-07
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Mines MA;Jope RS
• 通讯作者: Jope RS

Hyperactivity: glycogen synthase kinase-3 as a therapeutic target.

多动症：糖原合成酶激酶 3 作为治疗靶点。

• DOI: 10.1016/j.ejphar.2013.02.055
• 发表时间: 2013
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: Mines,MarjeloA

Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells.

• DOI: 10.1016/j.yexcr.2011.02.012
• 发表时间: 2011-07-01
• 期刊: EXPERIMENTAL CELL RESEARCH
• 影响因子: 3.7
• 作者: Meares, Gordon P.;Mines, Marjelo A.;Beurel, Eleonore;Eom, Tae-Yeon;Song, Ling;Zmijewska, Anna A.;Jope, Richard S.
• 通讯作者: Jope, Richard S.