Age related Differences in Chronic Rhinosinusitis and Nasal Polyps

慢性鼻窦炎和鼻息肉的年龄相关差异

• 批准号: 8900169
• 负责人: Seong Ho Cho
• 金额: $ 13.02万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900169
• 关键词: Adult; Age; Aging; Air; Antibiotics; Asthma; Autoantibodies; Autoimmune Process; Autoimmune Responses; Autoimmunity; Award; B-Cell Activation; B-Lymphocytes; Biological Markers; Cephalosporins; Chimeric Proteins; Chronic Disease; Clindamycin; Clinical; Clinical Management; Clinical Sciences; Clostridium difficile; Cohort Studies; Colitis; Communities; Culture Techniques; Death Rate; Defect; Development; Diagnosis; Disease; Elderly; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelium; Etiology; Faculty; Family; Fluoroquinolones; Functional disorder; Generations; Geriatrics; Goals; Health; Healthcare; High Prevalence; Host Defense; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunology; Incidence; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Link; Liquid substance; Modeling; Molecular Target; Mus; Nasal Polyps; Nose; Operative Surgical Procedures; Pathogenesis; Patients; Penicillins; Plasma Cells; Population; Population Study; Prevalence; Principal Investigator; Recombinants; Recruitment Activity; Recurrence; Reporting; Research Personnel; Resistance; Role; S100 Proteins; S100A7; S100A8 gene; STAT3 gene; Signal Transduction; Sinus; Steroids; Stimulus; Supervision; Symptoms; TNF gene; Testing; Therapeutic; Time; Tissues; Translational Research; United States; age group; age related; aged; anti-dsDNA antibodies; anti-dsDNA autoantibody; antimicrobial peptide; asthmatic patient; burden of illness; chronic rhinosinusitis; cohort; experience; inhibitor/antagonist; innate immune function; middle age; mouse model; new therapeutic target; novel; older patient; response; skills

DESCRIPTION (provided by applicant): The prevalence of chronic rhinosinusitis (CRS) sharply increases after age 50 such that those age 60 years and above are twice as likely to have CRS than adults age 19-39 years. A large cohort study in the US also shows that the incidence of CRS with nasal polyps (NP; CRSwNP) between ages 65-74 is almost two-fold higher compared with CRS without NP or control. CRSwNP in the elderly has not been well investigated despite the disease burden for geriatric patients and its impact on other common geriatric problems. During the clinical management of CRS, antibiotics remain widely prescribed, repeatedly or chronically, resulting in widespread emergence of resistant, often deadly bacterial strains in the community. Commonly used antibiotics in CRS are also the main causes of Clostridium difficile colitis which can be fatal in the elderly. The treatment of NP with antibiotics, steroids, and even surgery is often unsatisfactory, leading to a diagnosis of recalcitrant CRSwNP. This recalcitrant CRSwNP is further associated with severe and uncontrolled asthma which is another health care issue of the elderly population because older asthmatic patients are more likely to be hospitalized than younger asthmatic patients and they have the highest death rate of any other age group. Therefore there is a pressing unmet need to better understand the pathogenesis of CRSwNP in the elderly so that we may develop a new and effective therapeutic approach to manage this challenging clinical problem. After joining the Northwestern sinus center, the principal investigator (PI) started investigating age-related differences in the pathogenesis of CRS supported by the T. Franklin Williams Geriatrics Faculty Development Award and has made several important discoveries. The PI found that elderly CRS patients had more severe disease and higher prevalence of NP and asthma compared with the non-elderly in our study population and there was a significant positive correlation between anti-dsDNA autoantibodies in NP tissue and age, suggesting increased local autoimmune inflammation in the elderly. The B cell activating factor of the TNF family (BAFF) is highly elevated in CRS patients, especially in NP. This elevation of BAFF was highly correlated with increased numbers of B cells/plasma cells, and high levels of local immunoglobulins. This was primarily found in patients who had had multiple sinus surgeries, suggesting that recalcitrant forms of disease may be characterized by an autoimmune etiology. This local autoimmune inflammation in CRSwNP may be linked to epithelial barrier dysfunction and consequential bacterial/fungal colonization because there was significant reduction of epithelial-derived antimicrobial peptides, S100A7 and S100A8/9, in CRSwNP. The PI found that S100A8/A9 was further reduced in the elderly and inversely correlated with aging, which indicates pronounced epithelial barrier dysfunction in the elderly. Therefore, the central hypotheses of this proposal are that; 1) activation and expansion of B cells and plasma cells by BAFF leads to a pronounced autoimmune inflammatory response and generation of NP in the elderly, and; 2) an age-related decline of epithelial innate immune function contributes to persistent inflammation in the elderly with CRSwNP. These hypotheses will be examined in three Specific Aims. Aim 1. To determine whether elderly CRS patients have more extensive and recalcitrant disease due to pronounced B cell/plasma cell activation and local autoimmune responses, we will recruit a cohort of control (18-49), mature adult (50-64), young old (65-74), and advanced old (>75) patients with CRSwNP undergoing their first surgery (n=15 each) and compare the presence of BAFF, B cell, plasma cells, local immunoglobulins, and local autoantibodies in NP at the time of surgery. We will prospectively follow their clinical courses and biomarkers. Aim 2. To assess whether BAFF is critical for the formation of NP and determine if this changes with age, we will examine the degree of inflammation, B cell activation, and local autoimmune response in a murine model of CRSwNP in adult (2 months old), middle aged (12 months old), and aged (18 months old) mice. We will also treat mice with a BAFF inhibitor before or after NP generation in this model of CRSwNP with different ages, and investigate the effects of the BAFF inhibitor on histopathologic responses, generation of B cells, plasma cells, IgA/IgG, and anti-dsDNA antibodies. Aim 3. To determine whether nasal epithelial cells from the elderly have an impaired ability to produce the host defense molecules S100 proteins in response to various stimuli, we will obtain and culture nasal epithelial cells from different age groups with CRSwNP or healthy controls (n=15 each), and compare the innate ability to produce S1008/9 with or without various stimuli. We will further investigate the cellula mechanism to test for a defect in generation of total/phosphorylated STAT3, a signaling factor that controls innate immune responses in epithelium, in the elderly. This proposal will advance our understanding of age-related differences in the pathogenesis of CRSwNP, and will identify new therapeutic targets for CRSwNP in the elderly. This award will also greatly assist the PI to obtain translational research capabilities as well as develop skills to establish a new mouse model of CRSwNP for discovering novel molecular targets that are most promising for CRSwNP in the elderly. In Aim 1, selecting and recruiting elderly patients with CRS and following them prospectively will greatly enhance my knowledge and skills in translational and clinical science for the elderly. In Aim 2, I will establish a new murine model of CRSwNP under the supervision of Dr. Kim. In Aim 3, I will obtain new skills in culturing primary nasal epithelial cells from humn subjects including air-liquid interface culture techniques. My long-term goal through this award is to become an experienced independent investigator in aging and immunology.

描述（由申请人提供）：慢性鼻窦炎（CRS）的患病率在50岁以后急剧增加，因此60岁及以上的人患CRS的可能性是19-39岁成年人的两倍。美国的一项大型队列研究也表明，65-74岁CRS合并鼻息肉（NP; CRSwNP）的发生率几乎是没有NP或对照组CRS的两倍。尽管老年患者的疾病负担及其对其他常见老年问题的影响，但老年人的CRSwNP尚未得到很好的调查。在CRS的临床管理期间，抗生素仍然被广泛使用，反复或长期使用，导致社区中广泛出现耐药，通常是致命的细菌菌株。CRS中常用的抗生素也是难辨梭菌结肠炎的主要原因，而难辨梭菌结肠炎在老年人中是致命的。使用抗生素、类固醇甚至手术治疗NP往往不令人满意，导致诊断为顽固性CRSwNP。这种顽固性CRSwNP与严重和不受控制的哮喘进一步相关，这是老年人群的另一个卫生保健问题，因为老年哮喘患者比年轻哮喘患者更容易住院，他们的死亡率是其他年龄组中最高的。因此，迫切需要更好地了解老年人CRSwNP的发病机制，以便我们可以开发一种新的有效的治疗方法来处理这一具有挑战性的临床问题。在加入西北窦中心后，首席研究员（PI）开始研究CRS发病机制中的年龄相关差异，并得到T. Franklin Williams老年医学教师发展奖的支持，并取得了几项重要发现。PI发现，老年CRS患者与非老年人群相比，疾病更严重，NP和哮喘患病率更高，NP组织中抗dsdna自身抗体与年龄呈显著正相关，提示老年人局部自身免疫性炎症增加。TNF家族B细胞活化因子（BAFF）在CRS患者中高度升高，尤其是NP患者。BAFF的升高与B细胞/浆细胞数量的增加和局部免疫球蛋白的高水平高度相关。这主要是在多次鼻窦手术的患者中发现的，这表明顽固性疾病可能以自身免疫病因为特征。CRSwNP中的这种局部自身免疫性炎症可能与上皮屏障功能障碍和随之而来的细菌/真菌定植有关，因为CRSwNP中上皮来源的抗菌肽S100A7和S100A8/9显著减少。PI发现S100A8/A9在老年人中进一步降低，且与衰老呈负相关，说明老年人存在明显的上皮屏障功能障碍。因此，这一提议的中心假设是；1) BAFF对B细胞和浆细胞的激活和扩增导致老年人明显的自身免疫性炎症反应和NP的产生；2)与年龄相关的上皮先天免疫功能下降有助于老年CRSwNP患者持续炎症。这些假设将在三个具体目标中进行检验。目的1。为了确定老年CRS患者是否由于明显的B细胞/浆细胞活化和局部自身免疫反应而有更广泛和更顽固性的疾病，我们将招募对照组（18-49岁）、成熟成人（50-64岁）、年轻老年人（65-74岁）和晚期老年首次手术的CRSwNP患者（各15例），比较手术时NP中BAFF、B细胞、浆细胞、局部免疫球蛋白和局部自身抗体的存在。我们将前瞻性地跟踪他们的临床过程和生物标志物。目标2。为了评估BAFF是否对NP的形成至关重要，并确定其是否随着年龄的增长而变化，我们将在成年（2个月大）、中年（12个月大）和老年（18个月大）小鼠CRSwNP小鼠模型中检测炎症程度、B细胞活化和局部自身免疫反应。我们还将在不同年龄的CRSwNP模型中，在NP产生之前或之后用BAFF抑制剂处理小鼠，并研究BAFF抑制剂对组织病理反应、B细胞、浆细胞、IgA/IgG和抗dsdna抗体的产生的影响。目标3。为了确定老年人鼻上皮细胞在各种刺激下产生宿主防御分子S100蛋白的能力是否受损，我们将获得并培养来自不同年龄组的CRSwNP或健康对照（n=15）的鼻上皮细胞，并比较在各种刺激下或不刺激下产生S1008/9的先天能力。我们将进一步研究细胞机制，以检测老年人中总/磷酸化STAT3（一种控制上皮先天免疫反应的信号因子）产生的缺陷。这一建议将促进我们对CRSwNP发病机制中年龄相关差异的理解，并将确定老年人CRSwNP的新治疗靶点。该奖项还将极大地帮助PI获得转化研究能力，并发展建立新的CRSwNP小鼠模型的技能，以发现最有希望用于老年CRSwNP的新分子靶点。在Aim 1中，选择和招募老年CRS患者并对其进行前瞻性跟踪，将大大提高我在老年转化和临床科学方面的知识和技能。在Aim 2中，我将在Kim博士的指导下建立新的小鼠CRSwNP模型。在Aim 3中，我将获得培养人类受试者原代鼻上皮细胞的新技能，包括气液界面培养技术。通过这个奖项，我的长期目标是成为一名在衰老和免疫学方面经验丰富的独立研究者。