THE ENDOTHELIAL CELL IN PATHOGENESIS OF TTP

TTP发病机制中的内皮细胞

• 批准号: 6790631
• 负责人: JEFFREY C LAURENCE
• 金额: $ 33.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790631
• 关键词: HIV infections; apoptosis; cytokine; extracellular matrix; human tissue; ligands; nitric oxide; pathologic process; thrombocytopenic purpura; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION (Adapted from Investigator's Abstract): The hypothesis guiding this study is that microvascular endothelial cell (MVEC) apoptosis plays a key role in the pathophysiology of idiopathic and HIV-associated thrombotic thrombocytopenic purpura (TTP). It is also proposed that apoptosis is initiated by plasma factors up regulated in HIV and certain other infections, particularly soluble tumor necrosis factor-related ligand (TRAIL). It is furthermore proposed that these factors lead to alterations in MVEC-extracellular matrix (ECM) interactions and production of cytokines and vasoactive substances such as nitric oxide, all critical to MVEC survival. These concepts are supported by observations that: plasmas from HIV+ and HIV- patients with idiopathic and ticlopidine-linked TTP induce apoptosis in restricted lineages of MVEC, paralleling the EC tissue restriction of TTP lesions in vivo; plasma from patients with TTP or hemolytic-uremic syndromes related to cancer, marrow transplantation or other drugs, diseases distinct pathologically from idiopathic TTP, do not have these effects in vitro; apoptotic MVEC are present in splenic and marrow biopsies of idiopathic, HIV, and ticlopidine-linked TTP, accompanied by down regulation of ECM; and ticlopidine and HIV can directly affect ECM deposition and/or production. An additional recent finding is that MVEC-soluble HIV gp120-monocyte interactions up regulate TRAIL, TRAIL receptors, capsases 1 and 3, and suppress bcl-2-related molecules. Up regulation of bcl-2, anti-TRAIL antibody, or over expression of TRAIL decoys blocked TTP plasma-mediated apoptosis. The underlying hypothesis provides a basis for the clinical efficacy of anti-apoptotic agents and the nitric oxide precursor L-arginine in pilot trials for refractory TTP. The model presented could also enable exploration of new therapeutic modalities for TTP, based upon modulation of specific apoptotic pathways.

描述（根据调查员的摘要改编）：假设引导了这一点 研究是微血管内皮细胞（MVEC）凋亡起着关键作用 在特发性和HIV相关血栓形成的病理生理学中 血小板减少紫癜（TTP）。还提出了凋亡 通过血浆因素，在艾滋病毒和某些其他感染中调节的因素， 特别是可溶性肿瘤坏死因子相关配体（TRAIL）。这是 此外，提出这些因素导致了变化 MVEC-细胞基质（ECM）相互作用以及细胞因子的产生 血管活性物质，例如一氧化氮，都是MVEC存活至关重要的。 这些概念得到了：HIV+和HIV-的等离子体的观察支持。 特发性和钛连锁TTP的患者诱导凋亡 MVEC的限制谱系，与TTP的EC组织限制并行 体内病变； TTP或溶血性尿毒症综合征患者的血浆 与癌症，骨髓移植或其他药物有关，疾病不同 从特发性TTP的病理学上，在体外没有这些作用。 凋亡MVEC存在于特发性，艾滋病毒的脾和骨髓活检中 和ticlopidine连接的TTP，伴随着ECM的下调；和 Ticlopidine和HIV可以直接影响ECM沉积和/或生产。一个 最近的发现是MVEC可溶性HIV GP120单co型相互作用 向上调节步道，步道受体，1和3，并抑制 Bcl-2相关的分子。提高BCL-2，抗TRAIL抗体或以上的调节 诱饵的表达阻断了TTP等离子体介导的细胞凋亡。这 基本假设为临床疗效提供了基础 抗凋亡剂和初级试验中的一氧化氮前体L-精氨酸 对于难治性TTP。提出的模型还可以探索新的 基于特定凋亡的调节，TTP的治疗方式 途径。

项目成果

Repetitive and consistent cervicovaginal exposure to certain viral pathogens appears to protect against their sexual acquisition in some women: potential mechanisms.

反复且持续的子宫颈阴道暴露于某些病毒病原体似乎可以防止某些女性获得性行为：潜在机制。

• DOI: 10.1016/s0165-0378(02)00047-5
• 发表时间: 2003
• 期刊: Journal of reproductive immunology
• 影响因子: 3.4
• 作者: Laurence,Jeffrey

Synergistic interactions between interferon-gamma and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma-associated apoptosis.

干扰素-γ 和 TRAIL 之间的协同相互作用调节内皮细胞中的 c-FLIP，介导其对血栓性血小板减少性紫癜血浆相关细胞凋亡的谱系特异性敏感性。

• DOI: 10.1182/blood-2007-10-119552
• 发表时间: 2008
• 期刊: Blood
• 影响因子: 20.3
• 作者: Stefanescu,Radu;Bassett,Dustin;Modarresi,Rozbeh;Santiago,Francisco;Fakruddin,Mohamad;Laurence,Jeffrey
• 通讯作者: Laurence,Jeffrey

Endothelial cell apoptotic genes associated with the pathogenesis of thrombotic microangiopathies: an application of oligonucleotide genechip technology.

与血栓性微血管病发病机制相关的内皮细胞凋亡基因：寡核苷酸基因芯片技术的应用。

• DOI: 10.1006/mvre.2001.2326
• 发表时间: 2001
• 期刊: Microvascular research.
• 作者: Kim,J;Wu,H;Hawthorne,L;Rafii,S;Laurence,J
• 通讯作者: Laurence,J

'Reverse gear' cellular movement mediated by chemokines.

由趋化因子介导的“倒档”细胞运动。

• DOI: 10.1046/j.1440-1711.2001.01015.x
• 发表时间: 2001
• 期刊: Immunology and cell biology
• 影响因子: 4
• 作者: Zlatopolskiy,A;Laurence,J
• 通讯作者: Laurence,J

Interactions among human immunodeficiency virus (HIV)-1, interferon-gamma and receptor of activated NF-kappa B ligand (RANKL): implications for HIV pathogenesis.

人类免疫缺陷病毒 (HIV)-1、干扰素-γ 和活化 NF-κ B 配体受体 (RANKL) 之间的相互作用：对 HIV 发病机制的影响。

• DOI: 10.1111/j.1365-2249.2004.02568.x
• 发表时间: 2004
• 期刊: Clinical and experimental immunology.
• 作者: Fakruddin,JM;Laurence,J
• 通讯作者: Laurence,J