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A Genetic and Behavioral Model for the Human Response to Lithium

人类对锂反应的遗传和行为模型

基本信息

批准号：
7835754
负责人：
Todd D Gould
金额：
$ 18.75万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-07 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7835754
关键词：
Address Adverse effects Animal Model Animals Antidepressive Agents Antimanic Agents Behavioral Behavioral Model Biological Bipolar Disorder Brain Brain region Clinical Data Dextroamphetamine Disease Dissection Dose Drug Kinetics Functional disorder Future Generations Genes Genetic Genetic Variation Goals Human Human Genetics Incidence Individual Knowledge Lead Lithium Measures Mediating Metabolism Modeling Modification Molecular Molecular Target Monitor Mood Disorders Mood stabilizers Moods Mouse Strains Mus Neurobiology Patients Pattern Penetration Pharmaceutical Preparations Pharmacogenetics Pharmacological Treatment Pharmacology Population Positioning Attribute Process Publishing Relative (related person)Reporting Research Research Proposals Rodent Serum Signal Pathway Swimming Tail Suspension Testing Therapeutic Therapeutic Effect Time Treatment Efficacy Unipolar Depression Variant attenuation base behavioral pharmacology clinically relevant design effective intervention experience improved insight novel novel strategies pre-clinical prevent programs public health relevance relating to nervous system research study response therapeutic target tool trait

项目摘要

DESCRIPTION (provided by applicant): The combined lifetime population incidence of mood disorders, including bipolar disorder and unipolar depression, is over 15%. Many of these individuals do not receive optimized pharmacological treatment, which is influenced by the fact that the ability to predict patients who will respond to a particular drug is limited. The therapeutic efficacy of lithium for the treatment of mood disorders is well characterized. It is commonly used as a mood stabilizer, and in some patients as an antidepressant or adjunct antidepressant. However, despite extensive clinical use, it remains unclear exactly by what mechanism lithium exerts its therapeutic effects, and which patients can be optimally treated with lithium. This lack of knowledge is related to two specific clinical problems: 1) a restricted capacity to apply pharmacogenetic approaches to study genes associated with lithium response as well as predict prior to treatment which patients will respond to lithium, and 2) an inability to use a hypothesis driven approach to improve upon lithium's side- effect profile and narrow dose range with second-generation compounds. This research proposal is designed to characterize an animal model that will allow future studies to experimentally address the above problems. Inbred and outbred mice are commonly utilized in the field of behavioral pharmacology to evaluate effects of biological and genetic variations in behavioral models of medication responses. These differential behavioral patterns that manifest in different mouse strains have assisted in the characterization of essential neural processes and response to medications that are influenced by strain-dependent inheritable traits. However, despite over 50 years of clinical use and an unidentified mechanism of action, the use of mouse strain differences has not yet been fully employed in the study of the mood stabilizer- and antidepressant-like effects of lithium. The objective in this R21 application is to identify, and characterize behaviorally and pharmacologically, strains of mice that manifest distinct responses to lithium treatment in behavioral models. The Specific Aims are to: 1) Identify strains of mice with differential antidepressant-like effects of lithium, 2) Identify lithium pharmacokinetic correlates to the differential behavioral effects of lithium, and 3) Assess the mood stabilizer-like actions of lithium in individual strains by contrasting strain variation in models of antimanic vs. antidepressant efficacy. The mouse strain variations in lithium response characterized through the proposed research will likely lead directly to studies that will help define the target, and the underlying genetics, of lithium response. This new knowledge would ultimately lead to further optimization of treatment for patients who suffer from mood disorders. PUBLIC HEALTH RELEVANCE: Despite extensive clinical use of lithium for the treatment of mood disorders it remains unclear which patients will respond best to lithium and by what mechanism lithium exerts its therapeutic effects. It has therefore not been possible to improve upon lithium's side- effect profile and narrow dose range by developing novel medications that share the therapeutic target of lithium. This research proposal is designed to characterize a model that will assist future studies in experimentally determining the clinically relevant targets and underlying genetics of human response to lithium.

描述（由申请人提供）：心境障碍（包括双相情感障碍和单相抑郁症）的合并终生人群发病率超过15%。这些人中的许多人没有接受优化的药物治疗，这是由于预测患者对特定药物有反应的能力有限。锂用于治疗情绪障碍的疗效已得到充分表征。它通常用作情绪稳定剂，在某些患者中用作抗抑郁药或辅助抗抑郁药。然而，尽管广泛的临床应用，目前仍不清楚锂通过何种机制发挥其治疗作用，以及哪些患者可以用锂进行最佳治疗。这种知识的缺乏与两个具体的临床问题有关：1）应用药物遗传学方法来研究与锂反应相关的基因以及在治疗前预测哪些患者将对锂反应的能力有限，以及2）不能使用假设驱动的方法来改善锂的副作用特征和第二代化合物的窄剂量范围。本研究提案旨在描述动物模型的特征，使未来的研究能够通过实验解决上述问题。在行为药理学领域，通常使用近交和远交小鼠来评价药物反应行为模型中生物学和遗传变异的影响。这些表现在不同小鼠品系中的差异行为模式有助于表征基本神经过程和对受品系依赖性遗传性状影响的药物的反应。然而，尽管有超过50年的临床应用和未确定的作用机制，但小鼠品系差异的使用尚未完全用于锂的情绪稳定剂和抗抑郁剂样作用的研究。本R21应用的目的是鉴定和表征行为和行为学上的小鼠品系，这些小鼠品系在行为模型中对锂处理表现出不同的反应。具体目标是：1）鉴定具有锂的不同抗抑郁样作用的小鼠品系，2）鉴定与锂的不同行为作用相关的锂药代动力学，和3）通过对比抗躁狂与抗抑郁功效模型中的品系变化来评估锂在个体品系中的情绪稳定剂样作用。通过拟议的研究表征的锂反应的小鼠品系变化可能会直接导致有助于确定锂反应的目标和潜在遗传学的研究。这一新的知识最终将导致进一步优化对患有情绪障碍的患者的治疗。公共卫生相关性：尽管锂在临床上广泛用于治疗情绪障碍，但仍不清楚哪些患者对锂的反应最好，以及锂通过何种机制发挥其治疗作用。因此，不可能通过开发共享锂的治疗靶点的新型药物来改善锂的副作用特征和窄剂量范围。该研究提案旨在表征一种模型，该模型将有助于未来的研究在实验上确定临床相关目标和人类对锂反应的潜在遗传学。