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

描述(申请人提供)：骨髓抑制经常与人类病毒感染有关，包括巨细胞病毒、爱泼斯坦-巴尔病毒、人类疱疹病毒6和乙肝病毒，是移植后患者发病率和死亡率的重要原因。人类疱疹病毒8型(HHV8)，又称卡波西氏肉瘤相关疱疹病毒(KSHV)，此前已被认为与卡波西氏肉瘤、原发性渗出性淋巴瘤和多中心Castleman病的发生有关。最近的研究也将感染HHV-8与实体器官和干细胞移植受者的骨髓衰竭联系起来。然而，HHV8在骨髓衰竭发病机制中的确切作用机制尚不清楚。我们发现，K13是一种HHV8编码的vFLIP(病毒FLICE抑制蛋白)，是一种强大的核因子-kB途径的激活剂，此前已发现该通路与造血抑制有关。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HHV8相关的骨髓抑制的发病机制中发挥关键作用，并为开发针对这种疾病的分子靶向治疗提供了一个理想的候选者。这项应用的主要目标是使用体外和体内测试来检验上述假设。在目的1中，我们将在转基因小鼠的骨髓中表达K13，并研究其对造血的影响。在目标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，在目标3中，我们将测试K13诱导的核因子-β激活的抑制剂及其下游靶基因逆转其对造血的抑制作用的能力。我们相信，总的来说，这些研究不仅将有助于更好地了解病毒诱导的骨髓衰竭综合征，而且还将为未来核因子-kB抑制剂在这些疾病中的临床评估提供框架。在接受骨髓和实体器官移植的患者中，骨髓衰竭是常见的。这项研究将有助于更好地理解病毒感染导致移植患者骨髓衰竭的机制(S)，并提供新的治疗策略。

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.