Elucidating the signal transduction pathways regulating CCK-mediated adult hippocampal neurogenesis

阐明调节 CCK 介导的成人海马神经发生的信号转导途径

• 批准号: 9318587
• 负责人: Reid Hans Johnson Olsen
• 金额: $ 3.49万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318587
• 关键词: Address; Adult; Apoptotic; Astrocytes; Biological Assay; Brain; Calcium; Cell Death; Cell Proliferation; Cell Survival; Cells; Chemicals; Cholecystokinin; Cholecystokinin B Receptor; Cholecystokinin Receptor; Cytoplasmic Granules; Data; Development; Disease; Dose; Effectiveness; Electrophysiology (science); Epilepsy; Functional disorder; GABA Receptor; Genetic; Hippocampus (Brain); Human; Image; Immunohistochemistry; In Situ Hybridization; Injection of therapeutic agent; Label; Lead; Learning; Link; Mediating; Memory; Mental disorders; Microscopy; Mus; Myoepithelial cell; Nature; Neurobiology; Neurodegenerative Disorders; Neurologic Dysfunctions; Neuronal Plasticity; Neurons; Neuropeptides; Neurotransmitters; Parahippocampal Gyrus; Parvalbumins; Pathologic; Physiologic pulse; Population; Process; Proliferating; Regulation; Reporting; Role; Schizophrenia; Signal Transduction; Signal Transduction Pathway; Site; Staining method; Stains; Stimulus; System; Tail; Techniques; Testing; Therapeutic; Training; Transplantation; Traumatic Brain Injury; Veins; Viral; adult neurogenesis; dentate gyrus; designer receptors exclusively activated by designer drugs; exhaustion; experience; experimental study; gamma-Aminobutyric Acid; in vivo; knock-down; mouse model; nerve stem cell; neuroblast; neurogenesis; newborn neuron; novel; progenitor; public health relevance; retroviral-mediated; self-renewal; small hairpin RNA; tool

 DESCRIPTION (provided by applicant): Adult neurogenesis is implicated in both normal neurobiological processes such as learning and memory, and in contributing to pathological states in its dysfunction. This process is regulated by experience and neuronal activity (activity-dependent adult neurogenesis) through local and long-distance connections. However, the mechanisms that underly activity-dependent adult neurogenesis are poorly characterized, and this has impeded efforts to determine whether adult neurogenesis is causally linked to linked to processes such as learning and memory, or diseases such as epilepsy and schizophrenia. I have identified the neuropeptide cholecystokinin (CCK) as a putative regulator of adult neurogenesis. My preliminary data suggests adult neural stem cells express functional CCK2 receptors, and that activity of CCK-expressing neurons could promote the proliferation of adult neural stem cells and neural progenitors. In order to further investigate these findings, I will utilize a combination of in vivo manipulations, viral techniques, and immunohistochemistry to activate these cells and determine their influence on the proliferation of adult neural stem cells and neural progenitors, the survival of neural progenitors and immature neurons, and the maturation and integration of maturing newborn neurons. In addition, I will learn calcium imaging and electrophysiology techniques to study how CCK-cell activity acts on these developing cells. Finally, I will train in advanced microscopy techniques in order to quantify these effects. With these techniques, I will exhaustively characterize the influence of CCK-cell activity on these stages of adult neurogenesis. Understanding this process could also lead to advancements in treating neurodegenerative disorders, such as facilitating the the proliferation, maturation, and integration of transplanted neural stem cells in order to treat conditions such as traumatic brain injury. Understanding trophic signals (such as CCK) that promote proliferation, survival, and integration of newborn neurons could advance the effectiveness of this putative therapy. Taken together, this proposal will address a basic fundamental gap in neurobiology, as well as providing potentially translational findings for human therapeutics.

 描述（由申请人提供）：成人神经发生涉及正常的神经生物学过程，如学习和记忆，并有助于其功能障碍的病理状态。这一过程是由经验和神经元活动（活动依赖性成人神经发生）通过本地和远程连接进行调节。然而，活动依赖性成人神经发生的机制特征很差，这阻碍了确定成人神经发生是否与学习和记忆等过程或癫痫和精神分裂症等疾病有因果关系的努力。我已经确定了神经肽胆囊收缩素（CCK）作为成人神经发生的假定调节剂。我的初步数据表明，成人神经干细胞表达功能性CCK 2受体，CCK表达神经元的活性可以促进成人神经干细胞和神经祖细胞的增殖。为了进一步研究这些发现，我将利用体内操作，病毒技术和免疫组织化学的组合来激活这些细胞，并确定它们对成体神经干细胞和神经祖细胞增殖，神经祖细胞和未成熟神经元的存活以及成熟新生神经元的成熟和整合的影响。此外，我将学习钙成像和电生理技术，以研究CCK细胞活性如何作用于这些发育中的细胞。最后，我将培训先进的显微镜技术，以量化这些影响。通过这些技术，我将详尽地描述CCK细胞活性对成年神经发生这些阶段的影响。了解这一过程也可能导致治疗神经退行性疾病的进展，例如促进移植神经干细胞的增殖，成熟和整合，以治疗创伤性脑损伤等疾病。了解促进新生神经元增殖、存活和整合的营养信号（如CCK）可以提高这种假定疗法的有效性。总的来说，这项提案将解决神经生物学中的一个基本空白，并为人类治疗提供潜在的转化发现。