约瑟芬乐，医学博士

24个月前重返列表：医院

微血管内皮细胞是大脑中的许多过程的工具，包括给氧、屏障功能和炎症反应。；颅脑损伤后，血管紊乱导致血管收缩性，增加，和毛细血管闭塞，事件放大主侮辱。；这些内皮损伤反应的理解过程中脑损伤的神经保护策略的研究是非常重要的。；这个话题成为了我研究的一个主要地区。；

我也有兴趣在神经调节蛋白1（NRG1）在微血管内皮细胞的信号，特别是对血管内皮细胞通透性的影响。；NRG1基因是一种内源性生长因子，在胚胎发育和出生后的心功能和神经系统是非常重要的。；中枢神经系统，在nrg1s行动，通过4 ErbB受体介导的，有牵连，包括突触传递，髓鞘化，星形胶质细胞分化的不同神经元的突起，中间神经元的胚胎迁移和存活的神经元和星形胶质细胞亚群。；NRG1基因也被认为是精神分裂症的病理机制发挥作用。；在心脏病学领域，NRG1是探讨在临床试验中用于治疗慢性心脏衰竭。；NRG1表达为多个亚型，使许多不同的功能。；亚型用于这些研究NRG1与β；，目前研究最为广泛的基因亚型在脑研究。

罗博士的指导下工作的工程师，我的研究主要集中在三个主题- 1。在内皮细胞的通透性，改变白细胞粘附和血栓形成，细胞因子诱导的损伤；；2。神经调节蛋白-1的影响（NRG1）这些内皮细胞反应；3。NRG1的保护潜力。；这些调查是在细胞因子-细胞培养模型；损伤和缺氧缺糖，和一个体内 model of cortical contusion in mice。并；Relevant outcome parameters in endothelial permeability, neutrophil adhesion, and endogenous NRG1/erbB signaling are examined。 In the 体内 experiments, additional outcomes in motor and cognitive performance are examined。并；The effect of exogenous NRG1-β administration on these outcomes is also being investigated。

最初的实验是确定信令NRG1\/ErbB目前是否执行重要功能的脑微血管内皮细胞。；虽然NRG1基因功能研究了神经元、胶质细胞、内皮细胞和非中枢神经系统的起源，其在脑微血管内皮细胞的作用没有得到很好的定义。；；我们的工作提供的证据表明，NRG1和ErbB受体在脑微血管内皮细胞，并鉴定内皮通透性作为目标NRG1与β；；在信号。体外研究，NRG1与β；减少内皮细胞通透性增高的IL-1β和β诱导；；平行。体内使用一个控制大脑皮质的影响实验（CCI）在小鼠脑损伤模型，NRG1与β；治疗的小鼠急性血脑屏障（BBB）通透性降低相比，车辆处理过的小鼠。；此外，收到NRG1与β的小鼠；TBI后提高了认知结果与PBS处理控制。；

我们还研究了内皮细胞粘附分子的表达及中性粒细胞与内皮细胞粘附及后IL-1β；曝光。；果然，IL-1β和β；增加粘附分子的表达及中性粒细胞与内皮细胞的粘附。；NRG1与β共孵育；降低粘附分子VCAM-1和E-选择素在脑微血管内皮细胞已经由IL-1和β活性的表达，改善；IL-1和β；中性粒细胞黏附所致。；在神经炎症的情况下，这些措施可以显著NRG1过度的炎症反应，可以破坏后的存活细胞损伤。

脑外伤后取决于脑细胞之间的相互作用，不同类型的神经系统的结果。；因此我们探索相关主题的周细胞\/内皮细胞的相互作用，在神经元亚群的生存文化氧糖剥夺期间。

总之，我们的数据提供了证据表明NRG1与β；信号降低IL-1β和β；血管内皮通透性增大，粘附分子的表达，和中性粒细胞黏附。此外，NRG1与β静脉给药；提高外伤性脑损伤后小鼠的认知结果。；；；目前的实验目的是针对调查的途径通过NRG1与脑微血管内皮细胞以及这些相互作用如何可以改善创伤性脑损伤后的结果。

工具书类

乐J，王慧，村田Y，朱华，秦，惠伦MJ，瞧啊。；影响神经调节蛋白-1在小鼠组织病理及功能控制大脑皮质的影响后的结果。；J 2007 24:1817-1822创伤。乐J，萨尔迪SP、郭、贝桑松、哈Duy m，罗塞尔，基姆WJ，；corfas G，瞧啊。；神经调节蛋白-1在脑内皮细胞信号。；2009日jcbfm；29（1）：39-43。。收稿日期8月27日2008。乐J，赵，梁W，SEO JH，navaratna D，王X，惠伦MJ，瞧啊。；实验后1影响内皮损伤和血脑屏障通透性。；译卒中研究7月1日2012；3（S1）：s119-s124。收稿日期4月13日2012。郭、周Y、兴、乐J，SOM，宁米，集X，瞧啊。；对小鼠脑vasculome ；PLoS ONE。2012；7（12）。郭，乐J，刘Y，早川K，梁W，兴C，集X，瞧啊。检测内皮细胞迁移，管形成，基因表达谱。分子生物学方法。2014；1135:393-402 五、递送、梁W，赛克斯DB，吴健，瞧啊，乐J。 NRG1与β；降低IL-1和β；诱导的嗜中性粒细胞粘附到人脑微血管内皮细胞。翻译中风研究。 2014 May 28。

图1

图1。 Effects of并；NRG1-β并；on barrier integrity。并；(A) Trans-Endothelial Electrical Resistance (TEER) was measured continuously in primary human brain microvascular endothelial cells (BMEC) with increasing concentrations of NRG1: 10ng/ml, 30 ng/ml, 100ng/ml, 300 ng/ml, 600 ng/ml and 1200 ng/ml。并；After baseline steady-state TEER was achieved, the various concentrations of NRG1 were introduced at time = 0。并；The resistance was measured at 4000 Hz in 15 min intervals for the duration of the time shown。 (B) TEER (measured as above) from BMECs exposed to IL1β (100ng/ml) or IL1β (100ng/ml) added together with NRG1。并；TEER values are represented as the change (from baseline) in the average normalized TEER shown with the positive SEM (N= 3)。并；(C) Evaluation of BMEC viability after exposure to IL-1β (100ng/ml) alone or with either NRG1 at 100ng/ml or 300ng/ml。并；After formation of BMEC monolayers, the indicated experimental condition was added for 18 hr。并；The viability of the BMECs were evaluated by MTT assay (left axis) or LDH (right axis)。并；For the MTT results, the data is represented as the percent in cell viability when compared to the untreated control (shown as the mean + SEM)。并；For LDH, the results are expressed as the percentage of LDH release (shown as the mean + SEM)。并；This set of experiments was done in collaboration with Dr。 Servio Ramirez at Temple University。

Figure 2。并；NRG1-β reduces the IL-1β- induced increase in neutrophil adhesion to 人脑血管内皮细胞

In PBS-treated BMECs, an average of 14 (14 +/- 6。5) neutrophils were adherent to the endothelial monolayer in each high-powered (10x) field。 In IL-1β – treated endothelial cells, the number of adherent neutrophils increased to 35 (35+/- 12。9), a 2。5 fold increase (p<0。05)。 In BMECs treated with IL-1β and co-incubated with NRG1-β (100ng/ml or 12。5nM) NRG1-β, the number of adherent neutrophils decreased to the baseline level of 14 (14。6 +/- 4。7; p<0。05 when compared to BMECs treated with IL-1β and co-incubated with PBS)。 In endothelial cells treated with IL-1β and 300ng/ml (37。5nM) NRG1-β, the number of adherent neutrophils was 9。9 (9。9 +/- 4。0), again a significant decrease from that in cells treated with IL-1β without NRG1-β (p<0。05)。

图3

图3。并；Effect of NRG1 on probe trial performance after CCI。并；Vehicle-treated and NRG1- β treated mice were subjected to the MWM training and testing paradigm, starting on post-injury day14 after CCI。并；After 5 training sessions, retention and recall of spatial memory was evaluated in the probe trial, in which the amount of time that each mouse spent in the target quadrant was recorded。 (The target quadrant is the quadrant of the swim tank in which a previously hidden platform was located, and which the mice learned to associate with the platform over the course of the training sessions。) 并；NRG1-β treated mice had an improved performance in the probe trial, as evidenced by their preference for the target quadrant during the trial。