GRP78与 CHOP在缺血再灌注损伤中的作用

缺血再灌注（ischemia-reperfusion ,IR）过程中多种因素可导致内质网应激（endoplasmic reticulum stress response,ERS）, ERS参与缺血再灌注（ ischemia-reperfusion injury,IRI）的发展过程。总结ERS抗凋亡标志物GRP78与促凋亡标志物CHOP在IRI中的作用。 IRI时GRP78与CHOP表达的变化及其作用。明晰GRP78与CHOP参与IRI的机制。     

痿证中药方抑制线粒体内质网应激减轻大鼠脊髓损伤

目的 研究痿证中药方对脊髓损伤(SCI)大鼠模型中氧化应激反应及内质网应激相关蛋白表达的调节作用.方法 SPF级SD大鼠30只随机分为为假手术组、脊髓损伤模型组及痿证中药方组,痿证中药方组予以痿证中药方干预.术后第3～4天、1周、2周、3周、4周进行下肢运动功能评分,干预后30 d,取脊髓组织并采用HE染色法检测脊髄损...     

Overexpression of GRP78 protects glial cells from endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress induces apoptotic cell death by causing the accumulation of structurally abnormal proteins. The 78-kDa glucose-regulated protein (GRP78) is an ER chaperone that regulates protein folding in the ER and has been suggested to contribute to cell survival. Using the rat C6 glioma cell line and flow cytometry, we assessed GRP78 expression following tunicamycin- and glutamate-induced ER stress. The results showed that GRP78 expression is upregulated following ER stress and has protective effects on injured glial cells. Annexin V and propidium iodide labeling revealed cells transiently expressing GRP78 prior to injury were protected against high-concentrations of tunicamycin and glutamate within 72 h. Our findings support the hypothesis that GRP78 inhibits cell death associated with ER stress.     

Endoplasmic reticulum chaperone gp96 is essential for infection with vesicular stomatitis virus

The envelope glycoprotein of vesicular stomatitis virus (VSV-G) enables viral entry into hosts as distant as insects and vertebrates. Because of its ability to support infection of most, if not all, human cell types VSV-G is used in viral vectors for gene therapy. However, neither the receptor nor any specific host factor for VSV-G has been identified. Here we demonstrate that infection with VSV and innate immunity via Toll-like receptors (TLRs) require a shared component, the endoplasmic reticulum chaperone gp96. Cells without gp96 or with catalytically inactive gp96 do not bind VSV-G. The ubiquitous expression of gp96 is therefore essential for the remarkably broad tropism of VSV-G. Cells deficient in gp96 also lack functional TLRs, which suggests that pathogen-driven pressure for TLR-mediated immunity maintains the broad host range of VSV-G by positively selecting for the ubiquitous expression of gp96.     

Endoplasmic reticulum stress is activated in light-induced retinal degeneration

Exposure to excessive levels of light induces photoreceptor apoptosis and has previously been used as a model for the study of retinal degeneration. During the light exposure, intracellular calcium levels increase, and reactive oxygen species (ROS) are generated, which have been shown to cause endoplasmic reticulum (ER) stress. In the present study, we investigated the role of ER stress in light-induced photoreceptor apoptosis. Our study demonstrated that, after light exposure, the ER stress sensors including glucose-regulated protein-78 (GRP78/BiP), caspase-12, phospho-eukaryotic initiation factor 2 alpha (eIF2 alpha), and phospho-pancreatic ER kinase (PERK) were significantly up-regulated in a time-dependent manner. The up-regulation of these proteins coincided with or preceded the photoreceptor apoptosis indicated by TUNEL. These data showed that ER stress played an important role in light-induced photoreceptor apoptosis. Therefore, ER stress modulators could be strong candidates as therapeutic agents in the treatment of retinal degenerative diseases.     

MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress

MZB1 (pERp1) is a B-cell-specific and endoplasmic reticulum (ER)-localized protein implicated in antibody secretion and integrin-mediated cell adhesion. Here, we examine the role of MZB1 in vivo by conditional gene inactivation in the mouse germline and at different stages of B lymphopoiesis. Deletion of MZB1 impairs humoral immune responses and antibody secretion in plasma cells that naturally undergo ER stress. In addition, we found that experimental induction of ER stress by tunicamycin injections in mice results in a block of pro-B-cell to pre-B-cell differentiation specifically in Mzb1^−/− mice. A similar developmental block was observed in Mzb1^fl/flmb1^Cre mice, whereby a Cre recombinase-induced genotoxic stress unmasks a role for MZB1 in the surface expression of immunoglobulin µ heavy chains (µHCs). MZB1 associates directly with the substrate-specific chaperone GRP94 (also called HSP90B1 or gp96) in an ATP-sensitive manner and is required for the interaction of GRP94 with µHCs upon ER stress. Thus, MZB1 seems to act as a substrate-specific cochaperone of GRP94 that enables proper biosynthesis of µHCs under conditions of ER stress.     

Role of Endoplasmic Reticulum Stress in Rheumatoid Arthritis Pathogenesis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by abnormal proliferation of synoviocytes, leukocyte infiltration, and angiogenesis. The endoplasmic reticulum (ER) is the site of biosynthesis for all secreted and membrane proteins. The accumulation of unfolded proteins in the ER leads to a condition known as ER stress. Failure of the ER''s adaptive capacity results in abnormal activation of the unfolded protein response. Recently, we have demonstrated that ER stress-associated gene signatures are highly expressed in RA synovium and synovial cells. Mice with Grp78 haploinsufficiency exhibit the suppression of experimentally induced arthritis, suggesting that the ER chaperone GRP78 is crucial for RA pathogenesis. Moreover, increasing evidence has suggested that GRP78 participates in antibody generation, T cell proliferation, and pro-inflammatory cytokine production, and is therefore one of the potential therapeutic targets for RA. In this review, we discuss the putative, pathophysiological roles of ER stress and GRP78 in RA pathogenesis.     

Osteoporosis in children and young adults

Osteoporosis is a major public health problem with serious long-term complications. In children, the definition of osteoporosis is not only based on densitometric criteria but also takes into account vertebral and long bone fragility fractures. Several factors, such as long-term high-dose steroids, chronic inflammation, malnutrition, immobility, lack of sex steroids, and medication can reduce bone density and increase the risk for fragility fractures when left untreated. Also, genetic conditions can predispose to primary bone fragility disorders, with osteogenesis imperfecta being the most common. Furthermore, since the growing skeleton is at an increased rate of bone remodeling, the ability to heal long bone fractures and reshape vertebral fractures differentiates children from adults. The scope of this chapter is to review the risk factors of osteoporosis and fragility fractures and describe the commonest causes of primary and secondary osteoporosis and their management in children and young adults.     

人类白细胞抗原单倍体不合造血干细胞移植后自然杀伤性细胞和T淋巴细胞杀伤抑制性受体表达的研究

目的研究人类白细胞抗原(HLA)单倍体不合的造血干细胞移植后自然杀伤性细胞(NK细胞)和T淋巴细胞杀伤抑制性受体重建的规律。方法2004-04～2004-12对北京大学血液病研究所借助三色和四色荧光标记技术,用流式细胞仪对应用该所GIAC方案(即G:粒细胞集落刺激因子 I:强免疫抑制 A:抗胸腺细胞球蛋白 C:外周血与骨髓联合)进行HLA单倍体不合造血干细胞移植的24例患者(移植前、移植后 30、 60、 90、 120、 180d)及其供者外周血NK细胞及T细胞上杀伤免疫球蛋白类受体(KIR),包括CD158a(KIR2DL1)、CD158b(KIR2DL2)、CD158e(KIR3DL1)和Lectin样受体(CD94/NKG2A)的表达进行了测定。结果根据移植后NK细胞上受体重建规律不同可以分为两组:第1组在移植后 30d,与供者表达水平相比,病人受体表达明显升高(CD94,P=0.013;CD94∶NKG2A,P<0.0001;CD158e,P=0.063),随后逐渐下降,至 180d时重建为供者水平(CD158e、CD94)或仍明显高于供者水平(CD94∶NKG2A、P=0.001);第2组在移植后 30d,与供者表达水平相比,病人受体表达明显降低(CD158a,P=0.016;CD158b,P<0.003),随后逐渐升高,至正常供者水平。移植后患者外周血T淋巴细胞上杀伤抑制性受体的表达规律与NK细胞第1组相近,在 30和(或)60d时,所有KIR及CD94∶NKG2A的表达均明显高于正常供者水平,其后逐渐下降, 180d时降至正常供者水平(CD158a、CD158a/CD158b及CD158e)或仍明显高于供者水平(CD94/NKG2A,CD158b)。结论移植后NK细胞上KIR受体的低表达及CD94∶NKG2A的高表达可能是移植后早期NK细胞杀伤功能低下的主要影响因素;而移植后T细胞上KIR及CD94∶NKG2A的高表达可能有利于移植后的移植物抗宿主疾病(GVHD)及移植物抗白血病(GVL)效应分离。