Cyclic Nucleotide Regulation in Traumatic Brain Injury

描述（由申请人提供）：以前的研究强调，在脑和脊髓损伤后，第二信使环磷酸腺苷（cAMP）的水平显著降低，cAMP是神经元和炎症细胞中的关键细胞内信号分子。在过去的资助期间，我们的实验室发现，创伤性脑损伤（TBI）后cAMP减少参与创伤后脑对继发性损伤的脆弱性，如血流动力学改变，炎症和长期突触功能障碍。磷酸二酯酶4（PDE 4）是负责脑中cAMP水解的主要酶，并且目前是用于治疗包括神经创伤在内的各种人类神经系统疾病的重要分子靶标。我们在上一个资助期内完成的研究强调了不同PDE 4亚型对创伤反应的复杂性，即它们的各种时间依赖性细胞反应。这些细胞和生化变化的表征对于开发和检测针对特定PDE 4亚型的新抑制剂至关重要。在目前的提案中，我们将解决阻碍PDE4抑制剂治疗TBI的临床开发的几个知识空白，包括在特定炎症细胞群中鉴定PDE4亚型以及评估亚型选择性PDE4抑制剂对创伤后炎症的影响。另一个令人兴奋的最新发现是PDE4B亚型特异性抑制剂能够显着减少慢性认知缺陷，从而为TBI患者提供一种新的治疗策略。因此，根据我们以前和新的初步数据，我们提出以下四个目标：1）研究TOE4B对TBI后急性炎症的贡献，2）确定TBI后急性抑制TOE4B是否改善病理学和行为结果，3）测试TOE4B同种型选择性抑制剂是否改善慢性认知缺陷，最后，4）直接确定TOE4B的丧失是否改善TBI后的结果以及TOE4D的丧失是否影响TBI后的结果。这些研究将确定在TBI后的不同治疗时间窗需要选择性抑制哪些特定的PDE4亚型，以减少炎症和病理，并在三个治疗时间窗（急性，亚急性和慢性）中促进恢复。总之，这些研究将提供关于亚型选择性PDE4抑制剂产生其益处的精确细胞事件的关键信息，并提供基于证据的机制数据，以支持在TBI后的急性，亚急性和慢性治疗时间窗中使用PDE4抑制剂。该提案得到了一个多学科、多机构研究团队的支持，该团队在实验性TBI模型、PDE4B和PDE4D基因敲除小鼠方面具有丰富经验，并有一个药理学合作伙伴，在CNS药物发现方面有着既定的记录。这些研究将提供必要的临床前数据的临床翻译这些新的药物治疗外伤性脑损伤。

DESCRIPTION (provided by applicant): Previous studies have emphasized that after brain and spinal cord injury there are dramatic reductions in levels of the second messenger cyclic adenosine monophosphate (cAMP), a critical intracellular signaling molecule in neurons and inflammatory cells. Over the last funding period, our laboratory has found that after traumatic brain injury (TBI) cAMP reductions participate in the vulnerability of the posttraumatic brain to secondary injuries such as hemodynamic alterations, inflammation, and long-term synaptic dysfunction. Phosphodiesterase 4 (PDE4) is the major enzyme responsible for cAMP hydrolysis in the brain and currently is an important molecular target for the treatment of various human neurological diseases including neurotrauma. Studies we have completed during the previous funding period have emphasized the complexity of the response to trauma of different PDE4 isoforms in terms of their various time-dependent cellular responses. The characterization of these cellular and biochemical changes are critical for the development and testing of new inhibitors against specific PDE4 isoforms. In the current proposal, we will address several knowledge gaps that hamper clinical development of PDE4 inhibitors for the treatment of TBI, including the identification of PDE4 isoforms in specific inflammatory cell populations as well as assessing the effects on isoform-selective PDE4 inhibitors on posttraumatic inflammation. Another exciting recent discovery that will be investigated is the ability of PDE4B isoform-specific inhibitors to significantly reduce chronic cognitive deficits, thereby providing a novel therapeutic strategy for people living with TBI. Based on our previous and new preliminary data, we therefore propose the following four aims: 1) To investigate the contribution of PDE4B to acute inflammation after TBI, 2) To determine if inhibition of PDE4B acutely after TBI improves pathology and behavioral outcome, 3) To test whether a PDE4B isoform-selective inhibitor improves chronic cognitive deficits, and finally, 4) To directly determine if loss of PDE4B improves outcome and loss of PDE4D worsens outcome after TBI. These studies will determine which specific PDE4 isoforms need to be selectively inhibited at different therapeutic time windows after TBI to reduce inflammation and pathology, and promote recovery in three therapeutic time windows, acute, subacute and chronic. Together, these studies will provide critical information regarding the precise cellular events by which isoform-selective PDE4 inhibitors produce their benefits, and provide evidence-based mechanistic data to support the use of PDE4 inhibitors in acute, subacute, and chronic therapeutic time windows after TBI. This proposal is supported by a multidisciplinary, multi-institutional research team with experience in experimental TBI models, PDE4B and PDE4D knockout mice, and a pharmacological partner with an established record in CNS drug discovery. These studies will provide the necessary preclinical data for the clinical translation of these novel agents for the treatment of TBI.