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）是一种经常性的精神疾病，一生中至少遭受了至少6个美国人中大约1个。尽管原因可能是多因素的，但MDD的发作与海马中的结构缺陷相关，包括树突形态的改变。在MDD和MDD的动物模型中，刺激树突状生长的神经营养因素（例如脑衍生的神经营养因子（BDNF））的水平均降低。然而，尽管已知BDNF水平的降低与树突形态的改变相关，但BDNF刺激树突状生长的潜在信号传导机制尚不清楚。识别这些途径对于了解树突状发育和突触发生如何正常发生以及在MDD爆发过程中的改变至关重要。我们的远程目标是确定神经营养因子控制树突状发育的细胞内信号，并确定如何在正常和抑郁的大脑中调节这些信号。该应用的目的是确定一种临界神经营养因子BDNF控制树突形态发生，突触发生和维持突触结构的信号通路。我们的中心假设是，BDNF通过由临界蛋白质编码基因和非编码microRNA的基因组调节组成的协调反应刺激树突状发育，其在抑郁症过程中的表达会改变。我们已经根据已发布和未发表的数据提出了这一假设，该数据表明，蛋白质编码基因和非编码microRNA的CREB依赖性调节对于BDNF依赖性的树突状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，而且还抑制了抑制树突生长的途径。我们将以以下特定目的测试中心假设：1。确定CREB调节的蛋白质编码基因在BDNF刺激的树突状生长和突触发生中的要求。 2。确定在依赖BDNF的树突生长和突触发生中CREB调节的微RNA的需求。确定蛋白质编码基因和微RNA在正常发育过程中和BDNF表达改变期间的作用。我们将使用生化，遗传，细胞生物学，行为和成像方法来解决这些特定目标。拟议研究基础的基本原理是，一旦将BDNF与树突状和脊柱重塑联系起来的关键信号分子，他们就可以将其作为用于治疗和预防MDD的目标。这些研究之所以创新，是因为它们将PI在信号转导中的专业知识应用于关键和检查的问题：确定抑郁症过程中结构变化的分子机制。我们邀请了我们的顾问Jaak Panksepp的帮助，后者在研究抑郁症模型方面拥有丰富的经验。此外，由于树突状树皮化和旋转生成的异常是多种形式的智力低下，包括脆弱的X，Down和Rett综合征，因此这些结果预计将对该领域产生广泛的影响。 公共卫生相关性：拟议的研究与公共卫生有关，因为重大抑郁症（MDD）是一种使人衰弱的精神疾病，在生活中某个时候影响了六分之一的美国人。不幸的是，当前可用的抗抑郁药仅帮助MDD患者的子集（50-70％）。 MDD的发作与脑衍生的神经营养因子（BDNF）的水平降低有关。然而，尽管已知BDNF水平的降低与树突形态的改变相关，但BDNF刺激树突状生长的潜在信号传导机制尚不清楚。通过了解这些过程，我们为开发新疗法（例如遗传筛查，基因疗法和靶向药物设计）奠定了基础，以治疗MDD。