VPAC2 receptor function and its link to schizophrenia.

 描述(申请人提供)：精神分裂症是一种严重衰弱的疾病，影响全球1%的人口。尽管在过去的二十年里，在了解疾病的原因方面已经取得了重大进展，但我们仍然缺乏一个关于潜在机制的完整模型。最近，血管活性肠肽受体2(VPAC2R)区域基因拷贝数的增加被发现与精神分裂症密切相关。VPAC2受体是一种血管活性肠肽(VIP)反应性G蛋白偶联受体，主要通过cAMP信号通路传递信号。VPAC2受体在昼夜节律调节中的作用已经得到了很好的研究，但VIPR2在与心理健康和认知功能有关的神经元功能中的作用和机制尚不清楚。利用疾病相关基因拷贝数变异的动物模型，我将阐述VPAC2拷贝数变异如何引起与疾病相关的行为变化。VPAC2受体在海马区表达，它的激活增强了突触传递。在海马片中，我将确定海马区VPAC2受体的增强激活是否在VPACR拷贝数变化中是一种疾病机制，以及这是否导致长时程增强的变化。最后，使用基于DREADD的调制和对海马体电路的体内成像I将确定VPAC2受体信号在与恐惧条件反射行为相关的海马体电路中的作用，并揭示这种信号在疾病中是否被破坏。通过这项研究，我的目的是阐明从基因到行为的机制，VPAC2受体的增强表达可以促进精神分裂症的发生。这些发现将提高我们对VIP神经元间信号转导的潜在机制以及这与疾病相关行为精神分裂症的联系的理解，并使我们更接近这种疾病背后的生物学模型。我通过K01接受的培训将使我1)学习体外和体内生理学和行为方面的高级技能；2)获得解释这些技术所需的知识和分析工具；3)获得独立研究人员所需的能力。这个应用程序结合了教学、经验丰富的导师的指导和积极的研究，使我能够实现这些目标。在我所选择的导师团队的共同努力下，机构的支持提供了丰富的知识和专业知识，此次K01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，即成为一名致力于提高我们对精神分裂症的机制和治疗方法的理解的独立研究人员。

 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.