Role of vFLIP K13 in Bone Marrow Failure Syndrome Associated with Infection by Hu

vFLIP K13 在胡感染相关骨髓衰竭综合征中的作用

基本信息

批准号：
7420979
负责人：
Preet M. Chaudhary
金额：
$ 22.28万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-10 至 2009-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7420979
关键词：
Apoptosis Biological Assay Biological Process Bone Marrow Bone Marrow Suppression CASP8 and FADD-like apoptosis regulating protein CASP8 gene CD34 gene Cells Cessation of life Complex Complication Cytomegalovirus Development Differentiation and Growth Disease Failure Future Gene Targeting Goals Growth Hematopoietic Hematopoietic stem cells Hepatitis B Virus Herpesviridae Human Human Herpesvirus 4 Human Herpesvirus 8 Human Virus In Vitro Infection Investigation Kaposi Sarcoma Laboratories Lead Link Luc Gene Lymphoma Malignant Neoplasms Marrow Modeling Molecular Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia Mus NF-kappa B Names Open Reading Frames Organ Organ Transplantation Pancytopenia Pathogenesis Pathway interactions Patients Peripheral Blood Stem Cell Phosphotransferases Play Process Property Proteins Role Satellite Viruses Signal Pathway Solid Stem cell transplant Stem cells Structure Syndrome Testing Tetanus Helper Peptide Tetracycline Tetracyclines Transgenic Mice Transgenic Model Transplant Recipients Tumor Necrosis Factor Receptor Viral Viral Pathogenesis Viral Proteins Virus caspase-8 cytokine effusion in vivo inhibitor/antagonist insight mortality novel progenitor promoter receptor research clinical testing

项目摘要

DESCRIPTION (provided by applicant): Bone-marrow suppression is frequently seen in association with infection by human viruses, including the cytomegalovirus, Epstein-Barr virus, human herpes virus 6 and hepatitis B virus, and is an important cause of morbidity and mortality among post-transplant patients. Human herpes virus 8 (HHV8), also known as Kaposi's sarcoma associated herpes virus (KSHV), has been previously linked to the occurrence of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Recent studies have also linked infection with HHV-8 to bone marrow failure in solid-organ and stem cell transplant recipients. However, the exact mechanism of action of HHV8 in the pathogenesis of marrow failure is has not been characterized. We have discovered that K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein) is a strong activator of the NF-kB pathway, which has been previously linked to hematopoietic suppression. We have further demonstrated that K13 can upregulate the expression of cytokines with marrow suppressive properties. Thus, we believe that K13 may play a pivotal role in the pathogenesis of HHV8-associated marrow suppression and presents an ideal candidate for development of molecularly targeted therapies against this disorder. The primary goal of this application is to test the above hypotheses using in vitro and in vivo assays. In aim 1, we will express K13 in the marrow of transgenic mice and study its effect on hematopoieses. In aim 2, we will study the effect of K13 on the growth and proliferation of hematopoietic stem cells and progenitor cells. Finally, in aim 3, we will test the ability of inhibitors of K13-induced NF-?B activation and their downstream target genes to reverse its suppressive effect on hematopoieses. We believe that collectively these studies will not only lead to a better understanding of viral-induced marrow failure syndromes but will also provide the framework for future clinical evaluation of NF-kB inhibitors in these disorders. Bone marrow failure is frequently observed in patients undergoing bone marrow and solid-organ transplants. This study will lead to a better understanding of the mechanism(s) by which infection with viruses leads to bone marrow failure in transplant patients and provide new treatment strategies.

描述（由申请人提供）：经常看到与人类病毒感染相关的骨髓抑制，包括巨细胞病毒，爱泼斯坦 - 巴尔病毒，人疱疹病毒6和乙型肝炎病毒，是造成发病率和死亡率的重要原因移植后患者。人类疱疹病毒8（HHV8），也称为Kaposi的肉瘤相关疱疹病毒（KSHV），以前与Kaposi的肉瘤，主要积液淋巴瘤和多中性castleman病的发生有关。最近的研究还将HHV-8感染与固体器官和干细胞移植受者的骨髓衰竭联系起来。但是，尚未表征HHV8在骨髓衰竭发病机理中的确切作用机理。我们发现K13是HHV8编码的VFLIP（病毒抑制蛋白）是NF-KB途径的强激活因子，该途径先前已与造血抑制有关。我们进一步证明，K13可以上调具有骨髓抑制特性的细胞因子的表达。因此，我们认为K13可能在与HHV8相关的骨髓抑制的发病机理中起关键作用，并提出了开发针对该疾病的分子靶向疗法的理想候选者。该应用程序的主要目标是使用体外和体内测定测试上述假设。在AIM 1中，我们将在转基因小鼠的骨髓中表达K13，并研究其对造血的作用。在AIM 2中，我们将研究K13对造血干细胞和祖细胞生长和增殖的影响。最后，在AIM 3中，我们将测试K13诱导的NF-？B激活及其下游靶基因的抑制剂的能力，以逆转其对造血的抑制作用。我们认为，这些研究共同使人们对病毒诱导的骨髓衰竭综合症有了更好的了解，而且还将为这些疾病中NF-KB抑制剂的未来临床评估提供框架。接受骨髓和固体器官移植的患者经常观察到骨髓衰竭。这项研究将使人们对病毒感染导致移植患者的骨髓衰竭并提供新的治疗策略的机制有更好的了解。