Wnt/GSK3/beta Catenin Signaling as a Target for Treatment of Bipolar Disorder

Wnt/GSK3/β 连环蛋白信号传导作为双相情感障碍治疗的靶点

• 批准号: 7895297
• 负责人: Rakesh Karmacharya
• 金额: $ 18万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895297
• 关键词: Acetylation; Adverse effects; Affect; Antibodies; Award; Behavior; Biology; Bipolar Disorder; Brain; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Chemicals; Clinical; Data; Deacetylation; Development; Event; Fluorescence Microscopy; Functional disorder; Genes; Genetic Transcription; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; HDAC6 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Hospitals; Human; Image; Institutes; Laboratory Research; Lead; Literature; Lithium; Lysine; Manic; Measures; Mediating; Medical; Mental Depression; Mentors; Messenger RNA; Methods; Molecular; Moods; Mus; N-terminal; Neuroglia; Neurons; Nuclear; Nuclear Translocation; Oligodendroglia; Pathway interactions; Patients; Pharmaceutical Preparations; Phenocopy; Phosphorylation; Phosphorylation Site; Physicians; Play; Postdoctoral Fellow; Property; Protein Isoforms; Proteins; Psychiatry; Publishing; RNA Interference; Regulation; Research; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Rodent Model; Role; Schizophrenia; Scientist; Signal Pathway; Signal Transduction; Site; Synaptic plasticity; Therapeutic; Therapeutic Agents; Toxic effect; Training; Translations; Work; base; beta catenin; casein kinase I; chromatin immunoprecipitation; chromatin remodeling; clinically relevant; dopaminergic differentiation; dopaminergic neuron; experience; improved; inhibitor/antagonist; multicatalytic endopeptidase complex; nerve stem cell; neurogenesis; new therapeutic target; novel; novel strategies; programs; promoter; public health relevance; small molecule

DESCRIPTION (provided by applicant): The goal of the proposed research is to use a chemical biology approach to elucidate novel molecular mechanisms involved in the regulation of the Wnt/GSK3/beta-catenin signaling pathway, which is implicated in the pathophysiology and treatment of bipolar disorder. Recent work by the candidate showed that histone deacetylases (HDACs) play a role in modulation of beta-catenin levels. The candidate hypothesizes that specific histone deacetylase isoforms regulate beta-catenin levels and that elucidation of the mechanism(s) underlying HDAC regulation of beta-catenin levels will lead to a fundamental understanding of the Wnt signaling pathway and the identification of novel therapeutic targets for bipolar disorder. The research proposal aims to identify the specific HDAC isoforms that regulate beta-catenin levels, using RNAi against specific HDAC isoforms as well as novel isoform-specific HDAC inhibitors. The proposal aims to characterize mechanism(s) underlying HDAC modulation of beta-catenin signaling, by examining effects on chromatin remodeling as well as acetylation of lysine residues on beta-catenin itself. A systematic study of the lysine acetylation and the GSK-3 and casein kinase-1 (CK1) phosphorylation sites on beta-catenin will be conducted to delineate the temporal and regulatory effects of the phosphorylation and acetylation events. The proposal further aims to study the effects of beta-catenin modulating HDAC inhibitors on the proliferation and differentiation of human neural progenitor cells. The candidate is a physician-scientist with clinical training in psychiatry, with a focus on schizophrenia and bipolar disorder. He is currently conducting post-doctoral research in chemical biology, focusing on discovery of novel mechanisms that regulate beta-catenin signaling. His long-term goal is to establish and direct an academic research laboratory applying novel strategies in chemical biology to clinically-relevant challenges in bipolar disorder and schizophrenia. The proposed research will be carried out under the sponsorship of two mentors: Dr. Stuart L. Schreiber in the Chemical Biology Program at the Broad Institute of Harvard and MIT and Dr. Bruce M. Cohen in McLean Hospital. This award will support a unique training experience in clinically-informed research in chemical biology, and will establish an academic pathway for the discovery and development of experimental therapeutics for bipolar disorder and schizophrenia. PUBLIC HEALTH RELEVANCE: The development of improved therapeutics for bipolar disorder remains a significant unmet medical need. Identification of small molecules that regulate the Wnt-GSK-3/beta-catenin pathway through novel mechanims could lead to the development of alternative therapeutic agents with greater efficacy and reduced side effects compared to existing agents.

描述（由申请人提供）：拟议研究的目标是使用化学生物学方法阐明Wnt/GSK 3/β-连环蛋白信号通路调控中涉及的新分子机制，该信号通路与双相情感障碍的病理生理学和治疗有关。候选人最近的工作表明，组蛋白脱乙酰酶（HDAC）在β-连环蛋白水平的调节中发挥作用。候选人假设特定的组蛋白脱乙酰酶亚型调节β-连环蛋白水平，阐明HDAC调节β-连环蛋白水平的潜在机制将导致对Wnt信号通路的基本理解和双相情感障碍新治疗靶点的鉴定。 该研究计划旨在鉴定调节β-连环蛋白水平的特定HDAC亚型，使用针对特定HDAC亚型的RNAi以及新型亚型特异性HDAC抑制剂。该提案旨在通过检查对染色质重塑以及β-连环蛋白本身上赖氨酸残基的乙酰化的影响来表征HDAC调节β-连环蛋白信号传导的潜在机制。将对β-连环蛋白上的赖氨酸乙酰化和GSK-3和酪蛋白激酶-1（CK 1）磷酸化位点进行系统研究，以描述磷酸化和乙酰化事件的时间和调节作用。该提案进一步旨在研究β-连环蛋白调节HDAC抑制剂对人神经祖细胞增殖和分化的影响。 候选人是一名接受过精神病学临床培训的医生兼科学家，专注于精神分裂症和双相情感障碍。他目前正在进行化学生物学的博士后研究，重点是发现调节β-连环蛋白信号的新机制。他的长期目标是建立和指导一个学术研究实验室，将化学生物学中的新策略应用于双相情感障碍和精神分裂症的临床相关挑战。这项研究将在两位导师的赞助下进行：斯图尔特·L。Schreiber在哈佛和麻省理工学院布罗德研究所的化学生物学项目中以及布鲁斯·M·博士。姆克林医院的科恩 该奖项将支持化学生物学临床知情研究的独特培训经验，并将为双相情感障碍和精神分裂症的实验疗法的发现和开发建立学术途径。 公共卫生相关性：双相情感障碍的改良疗法的开发仍然是一个重大的未满足的医疗需求。通过新机制调节Wnt-GSK-3/β-连环蛋白途径的小分子的鉴定可能导致开发与现有药物相比具有更大功效和减少副作用的替代治疗药物。