Control of Dendritic and Synaptic Development by Extracellular Cues

细胞外信号对树突和突触发育的控制

• 批准号: 7783547
• 负责人: Gary Allen Wayman
• 金额: $ 36.72万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-02 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783547
• 关键词: Actins; Address; Affect; American; Animal Model; Antidepressive Agents; Behavior; Behavioral; Biochemical Genetics; Biological; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Cells; Code; Cues; Cytoskeleton; Data; Defect; Dendritic Spines; Depressed mood; Development; Drug Design; Event; Foundations; Fragile X Syndrome; Functional RNA; Gene Targeting; Genes; Genetic Screening; Genomics; Goals; Growth; Hippocampus (Brain); Human; Image; Life; Link; Maintenance; Major Depressive Disorder; Mental Depression; Mental Retardation; Mental disorders; MicroRNAs; Molecular; Morphogenesis; Morphology; Neurons; Pathway interactions; Patients; Pattern; Prevention; Process; Proteins; Public Health; Publishing; Recurrence; Regulation; Research; Rett Syndrome; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Study models; Synapses; Testing; Up-Regulation; Work; base; environmental enrichment for laboratory animals; experience; extracellular; gene function; gene therapy; in vivo; inhibitor/antagonist; innovation; neurotrophic factor; protein function; public health relevance; response; synaptogenesis

DESCRIPTION (PROVIDED BY APPLICANT): Major Depressive Disorder (MDD) is a recurrent mental illness that afflicts approximately 1 in 6 Americans at least once during their lifetime. While the causes are likely to be multi-factoral, the onset of MDD correlates with structural defects in the hippocampus, including alterations in dendritic morphology. The levels of neurotrophic factors like Brain Derived Neurotrophic Factor (BDNF), which stimulates dendritic growth, are decreased in both humans suffering from MDD and in animal models of MDD. However, while the decrease in BDNF levels is known to correlate with alterations in dendritic morphology, the underlying signaling mechanisms by which BDNF stimulates dendritic growth are unknown. Identifying these pathways is critical to understand how dendritic development and synaptogenesis occurs normally and how it is altered during bouts of MDD. Our long-range goal is to identify the intracellular signals by which neurotrophic factors control dendritic development and to determine how these signals are regulated in both normal and depressed brains. The objective of this application is to determine the signaling pathways by which one critical neurotrophic factor, BDNF, controls dendritic morphogenesis, synaptogenesis and the maintenance of synaptic structures. Our central hypothesis is that BDNF stimulates dendritic development via a coordinated response comprised of genomic regulation of both critical protein-coding genes and non-coding microRNAs whose expression are altered during depression. We have formulated this hypothesis on the basis of our published and unpublished data, which shows that an increase CREB dependent regulation of both protein coding genes and non-coding microRNAs are essential for BDNF dependent dendritic growth and synaptogenesis. The combination of these events not only activates pathways that promote dendritic growth but also inhibits pathways that suppress dendritic growth. We will test our central hypothesis with the following Specific Aims: 1. Determine the requirement of CREB regulated protein coding genes in BDNF-stimulated dendritic growth and synaptogenesis. 2. Determine the requirement for CREB regulated micro-RNAs in BDNF dependent dendritic growth and synaptogenesis. Determine the role of protein coding genes and micro-RNAs in vivo during normal development and during periods of altered BDNF expression. We will use biochemical, genetic, cell biological, behavioral and imaging approaches to address these specific aims. The rationale that underlies the proposed research is that once the critical signaling molecules linking BDNF to dendritic and spine remodeling become known they can be targeted for the treatment and prevention of MDD. These studies are innovative because they apply the expertise of the PI in signal transduction to a critical and under examined problem: to identify the molecular mechanisms underlying structural changes occurring during depression. We have enlisted the help of our consultant Jaak Panksepp, who has extensive experience in studying models of depression. Additionally, these results are expected to have a broad impact on the field as abnormalities in dendritic arborization and spinogenesis are common to numerous forms of mental retardation including Fragile X, Down's, and Rett syndromes. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because Major Depressive Disorder (MDD) is a debilitating mental illness that affects 1 in 6 Americans at some point in their lives. Unfortunately the currently available antidepressants only help a subset (50-70%) of patients with MDD. Onset of MDD is associated with a decrease in the levels of Brain Derived Neurotrophic Factor (BDNF). However, while the decrease in BDNF levels is known to correlate with alterations in dendritic morphology, the underlying signaling mechanisms by which BDNF stimulates dendritic growth are unknown. By understanding these processes, we are laying the foundation for the development of new therapies, such as genetic screens, gene therapies, and targeted drug design, to treat MDD.

描述（由申请人提供）：重度抑郁症 (MDD) 是一种反复发作的精神疾病，大约六分之一的美国人一生中至少遭受一次困扰。虽然原因可能是多因素的，但 MDD 的发病与海马体的结构缺陷有关，包括树突形态的改变。在患有重度抑郁症的人类和重度抑郁症动物模型中，神经营养因子（例如刺激树突生长的脑源性神经营养因子（BDNF））的水平均下降。然而，虽然已知 BDNF 水平的下降与树突形态的改变相关，但 BDNF 刺激树突生长的潜在信号机制尚不清楚。识别这些途径对于了解树突发育和突触发生如何正常发生以及在 MDD 发作期间如何改变至关重要。我们的长期目标是识别神经营养因子控制树突发育的细胞内信号，并确定这些信号在正常和抑郁大脑中的调节方式。本应用的目的是确定一种关键神经营养因子 BDNF 控制树突形态发生、突触发生和突触结构维持的信号传导途径。我们的中心假设是，BDNF 通过协调反应刺激树突发育，该反应包括关键蛋白编码基因和非编码 microRNA 的基因组调控，这些基因的表达在抑郁症期间发生改变。我们根据已发表和未发表的数据制定了这一假设，该假设表明，蛋白质编码基因和非编码 microRNA 的 CREB ​​依赖性调节的增加对于 BDNF 依赖性树突生长和突触发生至关重要。这些事件的组合不仅激活促进树突生长的途径，而且抑制抑制树突生长的途径。我们将通过以下具体目标来检验我们的中心假设： 1. 确定 CREB ​​调节的蛋白质编码基因在 BDNF 刺激的树突生长和突触发生中的需求。 2. 确定 BDNF 依赖性树突生长和突触发生对 CREB ​​调节的 micro-RNA 的需求。确定正常发育期间和 BDNF 表达改变期间体内蛋白质编码基因和 micro-RNA 的作用。我们将使用生化、遗传、细胞生物学、行为和成像方法来实现这些特定目标。这项研究的基本原理是，一旦了解连接 BDNF 与树突和脊柱重塑的关键信号分子，它们就可以成为治疗和预防 MDD 的目标。这些研究具有创新性，因为它们将 PI 在信号转导方面的专业知识应用于一个关键且尚未得到研究的问题：确定抑郁症期间发生的结构变化的分子机制。我们得到了顾问 Jaak Panksepp 的帮助，他在研究抑郁症模型方面拥有丰富的经验。此外，这些结果预计将对该领域产生广泛的影响，因为树突分枝和棘发生的异常是多种形式的精神发育迟滞的常见现象，包括脆性X、唐氏综合症和雷特综合症。 公共健康相关性：拟议的研究与公共健康相关，因为重度抑郁症 (MDD) 是一种使人衰弱的精神疾病，六分之一的美国人在生命中的某个阶段受到影响。不幸的是，目前可用的抗抑郁药只能帮助一小部分（50-70%）重度抑郁症患者。 MDD 的发病与脑源性神经营养因子 (BDNF) 水平的下降有关。然而，虽然已知 BDNF 水平的下降与树突形态的改变相关，但 BDNF 刺激树突生长的潜在信号机制尚不清楚。通过了解这些过程，我们为开发治疗重度抑郁症的新疗法奠定了基础，例如基因筛选、基因疗法和靶向药物设计。