Modeling stress-related psychopathology through FKBP5 manipulation

描述（由申请人提供）：在本修订申请中，我们将研究FK 506结合蛋白5（FKBP 5）如何上调以协调大脑如何响应压力。自2004年以来，我们的团队一直致力于证明FKBP 5基因中的单核苷酸多态性（SNP）与压力引起的精神病理学风险增加有关，如Nature Genetics 36：1319-25 2004 & JAMA 299：1291-305 2008中所强调的那样。我们还表明，这些风险SNP通过涉及FKBP 5基因去甲基化的机制增加FKBP 5的水平（Nature Neuroscience. 16：33-41 2013 & Journal of Clinical Investigation 123：4158-69 2013）。除了这些SNP之外，目前已知有2种其他机制增加脑中的FKBP 5水平：1）类固醇激素皮质醇（皮质酮/CORT）刺激糖皮质激素受体（GR），和2）调节受体酪氨酸激酶EphB 2（Attwood等人，Nature 473：372-5 2011）。在我们之前的工作中，我们发现缺乏FKBP 5基因的小鼠（FKBP 5-/-小鼠）受到保护，免受应激诱导的抑郁样表型的影响，除了这种改善的弹性外，这些小鼠似乎非常正常。杏仁核中FKBP 5的急性抑制也被证明可以保护小鼠免受焦虑样行为的影响，但我们对FKBP 5在大脑中的功能和调节的认识仍然存在空白。虽然我们知道FKBP 5确实会降低对压力的弹性，但我们不知道大脑中长期增加的FKBP 5水平是否可以通过类似于人类携带风险SNP的机制完全模拟受损的压力弹性。我们也不知道FKBP 5过表达如何影响学习和记忆，尽管压力和认知功能之间存在明确的联系。我们知道，慢性应激会破坏认知过程和神经元的电生理功能。但我们不知道应激诱导的认知、可塑性、海马体积或神经发生的缺陷是否由FKBP 5介导。最后，我们知道GR和EphB 2信号转导上调FKBP 5表达，我们还知道人类FKBP 5基因的去甲基化有助于FKBP 5上调。但我们不知道其他表观遗传修饰蛋白如何促进FKBP 5表达和去甲基化，也不知道EphB 2受体如何通过类似的甲基化机制调节FKBP 5表达。为了填补这些空白，我们将研究FKBP 5过表达对应激弹性和认知功能的影响，研究FKBP 5对慢性应激引起的认知和神经元缺陷的影响，并研究控制FKBP 5表达的机制。我们预计，这些研究将显示FKBP 5对大脑应激反应的重要性，从而对其在精神病理学和认知功能中的作用产生新的见解。我们还将定义FKBP 5表达的新的上游调节因子。

DESCRIPTION (provided by applicant): In this revised application, we will investigate how the FK506 binding protein 5 (FKBP5) is up- regulated to coordinate how the brain responds to stress. Since 2004, our team has worked to show that single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased risk of psychopathologies caused by stress, as highlighted in Nature Genetics 36:1319-25 2004 & JAMA 299:1291-305 2008. We have also shown that these risk SNPs increase the levels of FKBP5 through a mechanism that involves demethylation of the FKBP5 gene (Nature Neuroscience. 16:33-41 2013 & Journal of Clinical Investigation 123:4158-69 2013). There are currently 2 other mechanisms besides these SNPs that are known to increase FKBP5 levels in the brain: 1) Stimulation of the glucocorticoid receptor (GR) by the steroid hormone cortisol (corticosterone/CORT), and 2) modulation of the receptor tyrosine kinase EphB2 (Attwood et al. Nature 473:372-5 2011). In our previous work, we found that mice lacking the FKBP5 gene (FKBP5-/- mice) are protected from stress-induced depressive-like phenotypes, and that apart from this improved resiliency, these mice seem very normal. Acute suppression of FKBP5 in the amygdala has also been shown to protect mice from anxiety-like behavior, but there are still gaps in our knowledge about the function and regulation of FKBP5 in the brain. While we know that FKBP5 does reduce resiliency to stress, we do not know whether chronically increased FKBP5 levels in the brain can fully model impaired stress resiliency through a mechanism that is similar to humans carrying risk SNPs. We also do not know how FKBP5 overexpression impacts learning and memory despite clear connections between stress and cognitive function. We know that chronic stress disrupts cognitive processes and electrophysiological function of neurons. But we do not know if stress- induced deficits in cognition, plasticity, hippocampal volume or neurogenesis are mediated by FKBP5. Lastly, we know that FKBP5 expression is up-regulated by GR and EphB2 signaling, and we also know that demethylation of the FKBP5 gene in humans contributes to FKBP5 upregulation. But we do not know how other epigenetic modifying proteins contribute to FKBP5 expression and demethylation, nor do we know how the EphB2 receptor regulates FKBP5 expression through a similar methylation mechanism. To fill these gaps, we will examine the effects of FKBP5 overexpression on stress resiliency and cognitive function, examine the effects of FKBP5 on cognitive and neuronal deficits caused by chronic stress and investigate the mechanisms that control FKBP5 expression. We anticipate that these studies will show the importance of FKBP5 to the brain's stress response, leading to new insights about its role in psychopathologies and cognitive function. We will also define new upstream regulators of FKBP5 expression.