How does FVIII Expression Induce Cell Death

FVIII 表达如何诱导细胞死亡

基本信息

批准号：
8051763
负责人：
RANDAL J. KAUFMAN
金额：
$ 38.37万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8051763
关键词：
26S proteasome A-factor (Streptomyces)Animal Model Antioxidants Apoptosis Apoptotic Blood Circulation Blood Coagulation Factor Blood coagulation Calnexin Cell Death Cell Survival Cells Cellular Stress Chemicals Chronic Clinical Clinical Research Complex Cytosol Data Development Disease Endoplasmic Reticulum Event Exhibits Factor VIII Failure Gene Delivery Genes Genetic Genetic Transcription Golgi Apparatus Hemophilia A Hemorrhage Hepatocyte Immune response Individual Infectious Agent Inflammatory Response Inflammatory Response Pathway Infusion procedures Intervention Joints Life Mammalian Cell Mediating Mitochondria Molecular Chaperones Morbidity - disease rate Mutation Oxidative Stress Pathogenesis Pathway interactions Patients Plasma Problem Solving Production Proteins Reactive Oxygen Species Recombinants Research Role Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Intervention Treatment Efficacy Venous antibody inhibitor base biological adaptation to stress calreticulin cofactor cost endoplasmic reticulum stress experience factor C gene therapy improved inhibitor/antagonist insight mortality oxidative damage prevent protein folding protein misfolding recombinant antihemophilic factor VIII response transcription factor transcription factor CHOP

项目摘要

Accumulation of misfolded protein within the endoplasmic reticulum (ER) is a central event leading to cell death that contributes to disease pathogenesis. Although proteins exhibit oxidative damage in diverse disease states, the relationship between protein misfolding and oxidative stress has not been explored. To elucidate the relationship between protein misfolding and oxidative stress, we have analyzed expression of the clotting factor VIII (FVIII), the protein deficient in hemophilia A and prone to misfolding. Although hemophilia A patients are treated by frequent infusions of plasma-derived or recombinant-derived FVIII, significant limitations remain. It is hoped that FVIII gene therapy will solve these problems. Unfortunately, limited clinical studies have not demonstrated expression of FVIII at therapeutic levels. At the cellular level FVIII expression is limited due to protein misfolding and retention in the ER. As a consequence, FVIII expression induces transcription of ER stress response genes, through an intracellular signaling pathway called the unfolded protein response (UPR). Our studies have shown that the chronic unresolved accumulation of unfolded FVIII in the ER leads to apoptosis in a manner that requires the proapoptotic transcription factor C/EBP homologous protein CHOP. Recently, we have demonstrated that FVIII misfolding causes oxidative stress and induces an inflammatory response. In addition, oxidative stress causes FVIII misfolding, thereby creating a vicious cycle between FVIII misfolding and oxidative stress. Profoundly, anti-oxidant treatment to reduce oxidative stress improves FVIII secretion and reduces apoptosis. These findings provide the basis of the proposed research to elucidate how FVIII induces apoptotic, oxidative, and inflammatory response pathways. The studies will test the hypothesis that FVIII expression is limited due to induction of these stress responses. Studies will test whether intervention to prevent these toxic responses may improve therapeutic efficacy in FVIII gene delivery for hemophilia A. The findings from the proposed studies will provide fundamental new insights toward elucidating how protein misfolding in the ER signals a cell death response and should have impact on a number of disease states associated with ER stress.

内质网（ER）内错误折叠蛋白的积累是导致细胞的中心事件导致疾病发病机理的死亡。尽管蛋白质在多种多样表现出氧化损伤疾病状态下，尚未探索蛋白质错误折叠与氧化应激之间的关系。到阐明蛋白质错误折叠与氧化应激之间的关系，我们分析了凝血因子VIII（FVIII），蛋白质缺乏血友病A，容易折叠。虽然血友病A患者通过血浆衍生或重组衍生的FVIII频繁输注来治疗患者，仍然存在重大限制。希望FVIII基因疗法能够解决这些问题。很遗憾，有限的临床研究尚未证明在治疗水平上FVIII的表达。在细胞水平 FVIII表达受到蛋白质错误折叠和在ER中的保留而受到限制。结果，FVIII 表达通过细胞内信号通路诱导ER应力反应基因的转录称为展开的蛋白质反应（UPR）。我们的研究表明，慢性无法解决 ER中展开的FVIII的积累导致凋亡的凋亡方式转录因子C/EBP同源蛋白质。最近，我们证明了FVIII 错误折叠会导致氧化应激并诱导炎症反应。另外，氧化应激导致FVIII错误折叠，从而在FVIII错误折叠和氧化应激之间产生恶性循环。深刻的，抗氧化剂治疗以减少氧化应激可改善FVIII的分泌并减少凋亡。这些发现提供了拟议研究的基础，以阐明FVIII如何诱导凋亡，氧化和炎症反应途径。研究将检验FVIII的假设由于这些应力反应的诱导，表达受到限制。研究将测试干预是否预防这些有毒反应可以提高血友病的FVIII基因递送的治疗功效。拟议研究的发现将为阐明蛋白质的基本新见解提供基本的新见解 ER中的错误折叠信号表明细胞死亡反应，应对许多疾病状态产生影响与ER应力相关。