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

描述(由申请人提供)：痘病毒是一种皮肤营养DNA病毒，可导致严重的人类疾病，从轻微的局部皮肤感染(传染性软体病)到以泛发性脓疱疹(天花)为症状的灾难性全身疾病。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，以及皮肤导向抗痘病毒药物治疗的发展是重要的问题。目前可用的治疗人痘病毒感染的方法是相当有限和非特异性的。 这项建议详细说明了一项为期5年的培训计划，旨在发展皮肤病、痘病毒学和免疫学方面的学术生涯。在完成皮肤科临床培训和痘病毒学研究奖学金后，首席调查员(PI)将利用这段专门的时间获得成为独立研究人员所需的知识和技能。PI将由领先的病毒学家和生物化学家斯图尔特·舒曼博士和受人尊敬的免疫学家艾伦·霍顿博士指导，以探索痘病毒与皮肤免疫系统的接口，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。将提供充足的资源和多种职业发展活动，以帮助PI实现她的目标。 该建议的具体目的是：(I)利用转基因痘苗病毒剖析痘苗病毒如何与LCS/DC中的TLR信号转导以及核因子-β和干扰素途径交叉；确定抗痘病毒药物的分子靶点(S)；(Ii)评价人单核细胞来源的树突状细胞(MoDC)和浆细胞样树突状细胞(PDC)对痘苗病毒感染的免疫应答；(Iii)建立免疫低下小鼠皮肤感染模型；测试局部应用抗痘病毒药物的疗效。 这项研究有望对皮肤免疫系统如何应对痘病毒感染以及痘病毒如何通过关键信号通路实现免疫逃避产生新的知识和见解。它还将使我们能够开发新型抗痘病毒药物，并在活体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.