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: 8057786
• 负责人: MARJELO A MINES
• 金额: $ 3.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057786
• 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; Endoplasmic Reticulum; 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; Psychiatric therapeutic procedure; 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 （GSK3）在与精神疾病相关的细胞信号通路和行为表型中具有广泛的调节作用。此外，GSK3是一个可行的治疗靶点，因为GSK3抑制剂锂已经广泛用于治疗双相情感障碍，许多新的小分子选择性GSK3抑制剂正在开发中。三个特定的目标将探讨GSK3在应激细胞信号反应中的重要作用，GSK3的发育变化，以及GSK3在年轻和成年小鼠对兴奋剂的行为反应中的作用。这些目标不仅将提供关于GSK3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的职业规划很重要。内质网（ER）应激是由错误折叠蛋白的积累引起的，与许多疾病有关，并激活未折叠蛋白反应（UPR）和自噬。这些反应可以使细胞适应并在压力下存活，也可以导致细胞死亡，GSK3的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。特异性目的1将测试GSK3在内质网应激下调控UPR和自噬与凋亡平衡的机制。许多精神疾病是在发育过程中开始的，最近年轻人中精神疾病的患病率迅速增加，特别是在注意缺陷/多动障碍（ADHD）中。然而，目前还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，比如多动症，也不清楚在发育过程中服用的药物是否与成年人（大多数测试都是在成年人身上进行的）有同等的效果。特别令人感兴趣的是在ADHD治疗中普遍使用激活多巴胺能信号的兴奋剂。我们的实验室已经证明，3周龄和5周龄的小鼠大脑中GSK3的水平比成年小鼠高得多，这表明这可能在调节发育易感性方面发挥作用，并改变对激活GSK3的多巴胺能兴奋剂的反应。特异性目的2将在小鼠大脑中检测GSK3的发育变化及其在兴奋剂作用下的调节作用。安非他明治疗引起的多巴胺介导的过度活跃被GSK3抑制剂完全阻断，这表明安非他明后GSK3的激活对这种行为反应至关重要。特异性Aim 3将在小鼠中测试GSK3在发育过程中介导对刺激物的行为反应中的作用，并与成年小鼠进行比较。总之，这些目标将提供多学科培训，并将解决关键问题，以了解GSK3在细胞信号传导中对应激反应、发育过程和对广泛用于前成人的兴奋剂的反应中的调节作用。