The role of CIB1 on cutaneous papillomavirus replication and transcription

CIB1对皮肤乳头瘤病毒复制和转录的作用

• 批准号: 10542410
• 负责人: JENNIFER A LUFF
• 金额: $ 11.4万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542410
• 关键词: Affect; Animal Model; Binding Proteins; Binding Sites; Biopsy; Calcium Binding; Canis familiaris; Cells; Clinical; Cutaneous; Data; Development; Diagnosis; Disease; Epidermodysplasia Verruciformis; Evaluation; Foundations; Future; Genes; Genetic; Genetic Transcription; Goals; HIV; Host Defense; Human; Human Papillomavirus; IL2RG gene; Immunity; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunologics; Impairment; Individual; Infection; Infectious Skin Diseases; Inherited; Integrin Binding; Laboratories; Life Cycle Stages; Link; Malignant Neoplasms; Methods; Modality; Molecular; Mucous Membrane; Mutation; Operative Surgical Procedures; Organ Transplantation; Papillomavirus; Papillomavirus Infections; Pathogenesis; Patients; Persons; Phase; Predisposition; Quality of life; Rare Diseases; Refractory; Replication Origin; Research; Role; Site; Skin; Skin Cancer; Skin Carcinoma; Specimen; Study models; Sun Exposure; Tissues; Transcription Factor AP-1; Transplant Recipients; Viral; Virus Replication; canine model; cell type; chronic infection; cohort; congenital immunodeficiency; design; experimental study; gene repression; human disease; improved; keratinocyte; knock-down; mouse model; novel strategies; novel therapeutics; null mutation; overexpression; permissiveness; promoter; prophylactic; targeted treatment; therapeutic evaluation; vaccine development

Project Summary/Abstract Cutaneous papillomaviruses (PVs) can cause severe, persistent infections and skin cancer in immunodeficient patients. These patients include those with human immunodeficiency virus, organ transplants, and primary immunodeficiencies. Prophylactic PV vaccines developed to target mucosal PVs are not effective against cutaneous PVs, and treatments are limited and often ineffective. Thus, there is a critical need to identify targeted therapeutics for treatment of cutaneous PV infections and PV-associated skin cancers. Epidermodysplasia verruciformis (EV), a genodermatosis, offers a unique opportunity to study mechanisms of cell intrinsic host defense against PV in the skin, as these patients are highly susceptible to cutaneous PV infections but have no increased susceptibility to other infections. A recent study identified a cohort of EV patients with null mutations within calcium- and integrin-binding protein-1 (CIB1), as well as decreased CIB1 expression in EV-patients with other, more common, mutations that affect ~50% of EV patients. Collectively, these findings suggest that CIB1 is a key player in immunity to cutaneous PV infections and may act as a restriction factor against cutaneous PVs. EV, though, is a rare disease and thus obtaining clinical specimens for evaluation and future therapeutic testing is problematic. We have, however, discovered a naturally occurring EV-like disease in dogs which appears to mimic the human disease in several critical aspects: A) Like humans with EV, affected dogs acquire disseminated cutaneous PV infections that are refractory to treatment and can progress to cancer; B) Like humans, these dogs have restricted susceptibility to cutaneous PV infection; and C) Like humans, the disease occurs spontaneously. We propose the dog as a model for studying PV infections in immunocompromised patients. This could be the most valuable animal model to date to study not only the underlying pathogenesis of EV, but also identify conserved mechanisms of intrinsic keratinocyte defense against PV infections. Importantly, preliminary studies from our laboratory have demonstrated decreased expression of CIB1 in keratinocytes from EV-like dogs, highlighting a conserved mechanism underlying susceptibility to PV infections between humans and dogs, linked to CIB1. We hypothesize that impaired CIB1 expression enhances PV replication and transcription in keratinocytes in both humans and dogs with EV. In Aim 1, we will determine if CIB1 expression in impaired in dogs with EV-like disease, and in humans and dogs with another form of EV caused by IL2RG mutations. In Aim 2, we will determine if CIB1 expression regulates PV replication and transcription within keratinocytes, and if this is conserved between the dog and human. Using human PV and keratinocytes will address the human disease; using canine PV and keratinocytes will advance the dog model. Results will directly inform the next phase of experiments, and future R01 proposal, designed to elucidate molecular mechanisms of PV susceptibility in EV patients. With improved understanding of the molecular pathogenesis of these infections, targeted therapeutics may be further developed, which would ultimately improve the quality of life for patients with these devastating infections.

项目总结/摘要 皮肤乳头状瘤病毒（PV）可导致严重的，持续的感染和皮肤癌， 免疫缺陷患者。这些患者包括那些患有人类免疫缺陷病毒，器官移植， 原发性免疫缺陷针对粘膜PV开发的预防性PV疫苗对以下疾病无效： 皮肤肺静脉，治疗是有限的，往往无效。因此，迫切需要确定目标 用于治疗皮肤PV感染和PV相关皮肤癌的治疗剂。状表皮 疣状病毒（EV）是一种遗传性皮肤病，它为研究细胞内在宿主防御机制提供了一个独特的机会 针对皮肤中的PV，因为这些患者对皮肤PV感染高度敏感，但没有增加 易受其他感染。最近的一项研究确定了一组EV患者的钙内无效突变， 和整合素结合蛋白-1（CIB 1），以及CIB 1在EV患者中的表达降低， 常见的突变影响约50%的EV患者。总的来说，这些发现表明CIB 1是一个关键的球员， 对皮肤PV感染的免疫力，并可能作为对皮肤PV的限制因素。然而，EV是一个 罕见疾病，从而获得临床样本用于评估和未来的治疗测试是有问题的。我们 然而，在狗身上发现了一种自然发生的类似EV的疾病， 在几个关键方面的疾病：A）像人类EV，受影响的狗获得播散性皮肤PV 难以治疗并可能发展为癌症的感染; B）像人类一样，这些狗限制了 对皮肤PV感染的易感性;和C）与人类一样，该疾病自发发生。我们建议 狗作为研究免疫功能低下患者PV感染的模型。这可能是最有价值的动物 迄今为止的模型不仅研究EV的潜在发病机制，而且还确定了EV的保守机制。 针对PV感染的内在角质形成细胞防御。重要的是，我们实验室的初步研究 在EV样狗的角质形成细胞中，CIB 1的表达降低，突出了保守的 人类和狗之间对PV感染易感性的潜在机制，与CIB 1相关。我们假设 CIB 1表达受损可增强人和狗角质形成细胞中PV的复制和转录 关于EV在目标1中，我们将确定CIB 1表达是否在患有EV样疾病的狗和人类中受损。 以及患有由IL 2 RG突变引起的另一种形式EV的狗。在目标2中，我们将确定CIB 1表达是否 调节PV复制和角质形成细胞内的转录，如果这是狗和人之间的保守。 使用人PV和角质形成细胞将解决人类疾病;使用犬PV和角质形成细胞将解决人类疾病。 狗的模式。结果将直接通知下一阶段的实验，以及未来的R 01提案， 旨在阐明EV患者PV易感性的分子机制。随着人们对 这些感染的分子发病机制，靶向治疗可能会进一步发展， 最终改善这些毁灭性感染患者的生活质量。