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

基本信息

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
项目类别：
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

项目摘要

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）对与精神疾病相关的细胞信号传导途径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点，因为GSK3抑制剂锂已经广泛用于治疗双相情感障碍，并且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 在细胞应激反应中的重要作用、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有关 GSK3 与精神疾病之间联系的重要信息，还将为候选人提供多学科培训，这对于她建立专注于生物精神病学中生物医学问题的独立研究实验室的职业计划非常重要。内质网 (ER) 应激由错误折叠蛋白的积累引起，与许多疾病相关，并激活 UPR（未折叠蛋白反应）和自噬。这些反应可以让细胞适应并在压力下生存，或者可以导致细胞死亡，GSK3的抑制剂可以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 GSK3 调节 UPR 的机制以及 ER 应激中自噬与凋亡之间的平衡。许多精神疾病是在发育过程中引发的，最近年轻人精神疾病的患病率迅速增加，特别是注意力缺陷/多动障碍（ADHD）。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精神疾病，例如多动症，以及在发育过程中施用的药物是否与成人（大多数测试是在成人中进行）具有相同的效果。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传导的兴奋剂。我们的实验室表明，3 周龄和 5 周龄的小鼠大脑中 GSK3 水平比成年小鼠高得多，这表明这可能在调节发育敏感性中发挥作用，并改变对激活 GSK3 的多巴胺能兴奋剂的反应。具体目标 2 将在小鼠大脑中测试 GSK3 的发育变化及其受兴奋剂的调节。安非他明治疗引起的多巴胺介导的多动症可被 GSK3 抑制剂完全阻断，这表明安非他明后 GSK3 的激活对于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，GSK3 在介导发育过程中对兴奋剂的行为反应中的作用。总而言之，这些目标将提供多学科培训，并将解决对于理解 GSK3 在细胞信号传导中对压力、发育过程以及对广泛用于成人前的兴奋剂的反应中的调节作用至关重要的主题。公共卫生相关性：在美国，精神健康障碍是导致残疾的主要原因，占因残疾和过早死亡而损失的生命年数的 25%（NIMH 战略计划，2008 年）。在降低精神障碍的患病率和严重程度方面取得进展需要多种策略的结合。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，每个目标都由该项目的三个具体目标来解决。