Epigenetic Modulation Drives Chronic Type 2 Chronic Rhinosinusitis With Nasal Polyposis: Identifying Markers, Pathogens and Mechanisms
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Identification of epigenetic biomarkers and pathogenic viruses
研究概览
简要总结
Background/rationale
While multiple disorders feature a Type 2 (T2) inflammation, triggers for T2 remains unknown. In Chronic Rhinosinusitis with Nasal Polyposis CRSwNP), a classic Type 2 disorder, dysfunction of the epithelial barrier is suggested by loss of epithelial cell differentiation, impaired response to wounding, and impairment of innate defense mechanisms. After unsuccessful attempts to describe T2 disorders solely by host genetic or environmental factors, the role of epigenetics in the modification of innate immune response and epithelial integrity appears an important unexplored mechanism for a novel appreciation of T2 disease.
In addition, the investigators explore the possibility that these changes may be induced by viral pathogens. This concept has been supported by the recent observation that SARS-CoV-2 viral reduction measures resulted in a reduction of the frequency of respiratory viruses and a concomitant reduction in chronic airway disease, suggesting a role for viruses in T2 disease.
Hypothesis
The investigators believe T2 chronic rhinosinusitis (CRSwNP) involves epigenetic mechanisms where external factors, possibly viruses, contribute to disease via epigenetic manipulation and/or chronic viral infection.
Objectives
The investigators aim to identify epigenetic signatures associated with T2 CRS and explore the contribution of viruses. Method A robust methylation profiling with extensive coverage will be used for epigenome-wide association studies in T2 CRS patients assessing healthy subjects, CRS patients in remission, and diseased patients undergoing surgery. Moreover, advanced transcriptomic and metagenomic methods will identify gene expression profiles and viruses. This proposal also includes a cross-sectional study of patients undergoing surgery to assess transcriptomic patterns and epigenetics at the single-cell level.
Expected outcome
The investigators expect to identify epigenetic biomarkers and implicate several pathogenic viruses to open new targets for novel therapies.
详细描述
RESEARCH BACKGROUND & RATIONALE
Chronic rhinosinusitis (CRS) can manifest as T2 and/or non-T2 inflammation patterns, independently of the presence or absence of nasal polyps (NP). Certain aspects of CRS, such as NP formation, have been associated with epigenetic processes. Numerous studies support a role for epigenetics in the development and chronicity of other T2 diseases e.g. asthma and allergic rhinitis (North, Ann Allergy Asthma Immunol, 2011).
An insight into T2 disease pathogenesis may have been afforded by the "real-world" experiences during the COVID19 pandemic. Viral containment measures deployed in 2020 predictably reduced the frequency of most common respiratory viruses, reducing invasive respiratory infections along with exacerbations of asthma and COPD, which are typically triggered by viral respiratory infections (Linden, Eur Respir Rev, 2019; Mikhail, Ann Allergy Asthma Immunol, 2019). Unexpectedly, chronic inflammation of the upper airways was also reduced. Chronic otitis media with effusion and adenoiditis plummeted, and over half of the children on the waiting list for surgery the investigators removed because of spontaneous improvement. This was accompanied by anecdotal observations of a reduction in consultations for chronic rhinosinusitis with nasal polyposis (CRSwNP).
The investigators thus propose that T2 disease represents a unique facet of the inflammatory disease spectrum whereby dysfunction develops following interaction with a viral pathogen maintaining persistent effects via epigenetic mechanisms or chronic infection.
Detailed Research Plan Current understanding of T2 disease pathophysiology leaves early steps of pathogenesis largely unexplained. The investigators believe T2 disease is a result of epigenetic imprinting which reduces T1 response to injury or pathogens via impairment of Interferon (IFN) signaling components, leading to unopposed T2 signaling.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •T2 CRSwNP patients with favorable evolution
- •T2 CRSwNP patients undergoing ESS
- •Healthy volonteers with no nasal symptoms and documented normal sense of smell
排除标准
- •Cystic fibrosis
- •Primary immunodefisciencies
研究组 & 干预措施
Primary epithelial cells
Population: The investigators will use frozen dissociated cells from our biobank in earliest possible format (P0 or P1) to preserve original viruses and epigenetic marks. Polyp samples from T2 CRSwNP will be selected according to clinical phenotype together with blood test and histology.
Patients in remission of CRSwNP
Population: Perfect sinus cavity outcome after ESS under continued intranasal corticosteroids (INCS) or dupilumab.
Effect of sinus surgery on the sinus virome
Population: Patients undergoing ESS for CRSwNP, including at least 30% of subjects with aspirin sensitivity.
干预措施: Endoscopic sinus surgery (ESS) (Procedure)
Healthy volonteers
Population: Participants with no sino-nasal symptoms and normal sense of smell as assessed by UPSIT-40 testing.
结局指标
主要结局
Identification of epigenetic biomarkers and pathogenic viruses
时间窗: 12 months
The investigators expect to identify viruses and epigenetic markers associated with CRS. Viruses will be identified using bulk sequencing of collected tissue. Viruses will be considered "present" only if they are seen on at least 5 reads in sequencing. These identified viruses will be considered as associated with disease or healthy states assessed only when they are seen in at least 25% of tissue samples for the given condition. Association with disease will be defined as a higher proportion of candidate virus in diseased as opposed to healthy conditions. Epigenetic markers will be identified by comparing methylation profiles across the whole genome between active CRSwNP disease with disease in remission. Machine learning techniques will be used to identify putative sequences of epigenetic biomarkers associated with active disease or presence of an identified viral pathogen.
次要结局
未报告次要终点