Poxvirus interface with skin immune system, development of anti-poxvirus drugs

描述（由申请方提供）：痘病毒是一种皮肤营养性DNA病毒，可引起人类疾病，严重程度从轻度局部皮肤感染（传染性软疣）到以全身性脓疱皮疹（天花）为信号的灾难性全身性疾病。了解痘病毒的发病机制，特别是它与皮肤免疫系统的相互作用，以及开发皮肤定向抗痘病毒药物治疗是重要的问题。目前可用于人类痘病毒感染的治疗方法非常有限且非特异性。 该提案详细介绍了一个为期5年的培训计划，用于研究皮肤病学，痘病毒学和免疫学的学术生涯的发展。在完成皮肤病学的临床培训和痘病毒学的研究奖学金后，主要研究者（PI）将利用这段时间获得成为独立研究员所需的知识和技能。PI将由领先的痘病毒学家和生物化学家Stewart Shuman博士和受人尊敬的免疫学家Alan霍顿博士指导，以探索痘病毒与皮肤免疫系统的界面，并开发新型抗痘病毒药物。纪念斯隆-凯特琳癌症中心将提供机构支持。充足的资源和多种职业发展活动将可帮助PI实现其目标。 该提案的具体目标是（i）使用基因修饰的牛痘病毒来剖析牛痘病毒如何与TLR信号传导和NF-？LC/DC中的B和IFN途径;确定抗痘病毒药物的分子靶点;（ii）评估人单核细胞衍生的DC（moDC）和浆细胞样DC（pDC）对牛痘病毒感染的免疫应答;（iii）在免疫受损小鼠中建立皮肤感染模型;测试局部应用抗痘病毒药物的功效。 这项研究有望产生新的知识和见解，了解皮肤免疫系统如何对痘病毒感染作出反应，以及痘病毒如何与关键信号通路交叉以实现免疫逃避。这也将使我们能够开发新的抗痘病毒药物，并在体内小鼠皮肤模型中进行测试。

DESCRIPTION (provided by applicant): Poxviruses are dermatotrophic DNA viruses that cause human diseases ranging in severity from a mild local skin infection (molluscum contagiosum) to a catastrophic systemic illness signaled by a generalized pustular rash (smallpox). Understanding poxvirus pathogenesis, particularly its interaction with skin immune system, and the development of skin directed antipoxvirus drug therapy are important issues. The current available therapeutics for human poxvirus infections are quite limited and non-specific. This proposal details a 5-year training program for the development of an academic career in investigative dermatology, poxvirology and immunology. Having completed clinical training in dermatology and a research fellowship in poxvirology, the Principal Investigator (PI) will use this dedicated period to acquire the knowledge and skills necessary to become an independent researcher. The PI will be mentored by a leading poxvirologist and biochemist, Dr. Stewart Shuman, and an esteemed immunologist, Dr. Alan Houghton to explore the interface of poxvirus with skin immune system and to develop novel anti-poxvirus drugs. The Memorial Sloan-Kettering Cancer Center will provide institutional support. Ample resources and multiple career developmental activities will be available to help the PI to achieve her goals. The specific aims of the proposal are to (i) Use genetically modified vaccinia virus to dissect how vaccinia virus intersects TLR signaling, and the NF-?B and IFN pathways in LCs/DCs; Determine the molecular targets for antipoxvirus drug(s); (ii) Evaluate the immunological responses of human monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) to vaccinia virus infection; (iii) Establish a skin infection model in immunocompromised mice; Test the efficacy of topical application of antipoxvirus drugs. This study is expected to generate new knowledge and insights into how skin immune system responds to poxvirus infection and how poxvirus intersects key signaling pathways to achieve immune evasion. It will also allow us to develop novel antipoxvirus drugs and test them in an in vivo mouse skin model.