VPAC2 receptor function and its link to schizophrenia.

 描述（由申请人提供）：精神分裂症是一种严重的衰弱性疾病，影响全球1%的人口。虽然在过去二十年中，在了解疾病的原因方面取得了重大进展，但我们仍然缺乏一个完整的基本机制模型。最近，血管活性肠肽受体2（VPAC 2 R）区域基因拷贝数的增加被发现与精神分裂症密切相关。VPAC 2受体是血管活性肠肽（VIP）响应性G蛋白偶联受体，其主要通过cAMP信号传导途径进行信号传导。VPAC 2受体在昼夜节律调节中的作用已经得到了很好的研究，但VIPR 2在与心理健康和认知功能相关的神经元功能中的作用和机制仍然未被探索。使用疾病相关遗传拷贝数变异的动物模型，我将讨论VPAC 2拷贝数变异如何引起与疾病相关的行为变化。VPAC 2受体在海马中表达，其激活增强突触传递。在海马切片中，我将确定海马中VPAC 2受体的增强激活是否是VPACR拷贝数变异的疾病机制，以及这是否会导致长时程增强的变化。最后，使用基于DREADD的调制和海马电路的体内成像，我将确定与恐惧条件反射行为相关的海马电路中VPAC 2受体信号传导的作用，并揭示这是否在疾病中被破坏。通过这项研究，我的目的是阐明机制，从基因到行为，通过增强VPAC 2受体的表达可以有助于精神分裂症。这些发现将提高我们对VIP中间神经元信号传导的潜在机制的理解，以及这种机制如何与疾病相关的行为精神分裂症联系在一起，并使我们更接近这种疾病的生物学基础的更完整模型。我通过这个K 01的培训将使我能够1）学习体外和体内生理学和行为的高级技能; 2）获得解释这些技术所需的知识和分析工具; 3）获得独立调查员所需的能力。该应用程序集成了教学，经验丰富的导师和积极的研究指导，让我实现这些目标。与我选择的导师团队一起，机构支持提供了丰富的知识和专业知识，K 01奖的支持将使我能够实现这些目标，并使我更接近我的长期职业目标，即成为一名独立的研究者，致力于提高我们对精神分裂症机制和疗法的理解。

 DESCRIPTION (provided by applicant): Schizophrenia is a severely debilitating disease affecting 1% of the population worldwide. Though major progress has been made in the last two decades towards understanding the causes of the disease, we still lack a complete model for the underlying mechanisms. Recently, increases in the number of gene copies in the Vasoactive Intestinal Peptide Receptor 2 (VPAC2R) region were found to be strongly linked to schizophrenia. The VPAC2 receptor is a vasoactive intestinal peptide (VIP) responsive G-protein coupled receptor which signals predominantly through the cAMP signaling pathway. The role of the VPAC2 receptor in the regulation of circadian rhythm has been well studied, but the role and mechanism of VIPR2 in neuronal functions linked to mental health and cognitive function remains unexplored. Using animal models of disease-linked genetic copy number variation, I will address how VPAC2 copy number variations give rise to behavioral changes linked with disease. The VPAC2 receptor is expressed in the hippocampus and its activation enhances synaptic transmission. In hippocampal slices I will determine whether enhanced activation of VPAC2 receptors in the hippocampus presents a disease mechanism in VPACR copy number variation, and if this leads to changes long term potentiation. Finally, using DREADD based modulation, and in-vivo imaging of hippocampal circuitry I will determine the role of VPAC2 receptor signaling in hippocampal circuitry linked to fear conditioning behavior and reveal whether this is disrupted in disease. Through this research I aim to illuminate the mechanisms, from gene to behavior, by which enhanced expression of the VPAC2 receptor can contribute to schizophrenia. These findings will improve our understanding of the underlying mechanisms of VIP interneuron signaling and how this links to disease-related behavior schizophrenia and bring us closer to a more complete model of the biology underlying this disease. My training through this K01 will allow me to 1) learn advanced skills in in-vitro and in-vivo physiology and behavior; 2) gain the knowledge and analysis tools required to interpret these techniques; and 3) acquire the capabilities required of an independent investigator. The application integrates didactic teaching, mentorship from experienced mentors and active research to allow me to achieve these goals. Together the mentorship team I have selected, the institutional support provided a wealth of knowledge and expertise and the support of this K01 Award will allow me to achieve these goals and bring me closer to my long term career goal of becoming an independent investigator dedicated to improving our understanding of mechanisms and therapies in schizophrenia.