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: 9130093
• 负责人: Seong Ho Cho
• 金额: $ 13.04万
• 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/9130093
• 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; Diagnosis; Disease; Elderly; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelium; Etiology; 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; 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; Teacher Professional Development; 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; study population

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）：50岁以后，慢性鼻孔炎（CRS）的患病率急剧增加，使得60岁及以上的人患有CRS的可能性是19-39岁的成年人的两倍。在美国进行的一项大型队列研究还表明，与没有NP或对照的CR相比，在65-74岁之间具有鼻息（NP； CRSWNP）的CRS的发生率几乎高两倍。尽管老年患者的疾病负担及其对其他常见的老年问题的影响，但老年人的CRSWNP尚未得到很好的研究。在CRS的临床管理期间，抗生素在社区中反复或慢性地处开处方，导致社区中耐药性，致命的细菌菌株的广泛出现。 CRS中常用的抗生素也是艰难梭菌结肠炎的主要原因，这可能是老年人致命的。用抗生素，类固醇甚至手术治疗NP通常不令人满意，从而诊断出顽固的CRSWNP。这种顽强的CRSWNP与严重和不受控制的哮喘进一步有关，这是老年人口的另一个医疗保健问题，因为年龄较大的哮喘患者比年轻的哮喘患者更可能住院，并且在任何其他年龄段的死亡率最高。因此，不满意的需要更好地了解老年人中CRSWNP的发病机理，以便我们可以开发一种新的有效的治疗方法来解决这一具有挑战性的临床问题。加入西北鼻窦中心后，首席研究员（PI）开始调查与T. Franklin Williams老年院长发展奖CRS发病机理中与年龄相关的差异，并做出了一些重要发现。 PI发现，与我们的研究人群中的非大率相比，老年CRS患者患有更严重的NP和哮喘患病率，NP和哮喘患病率更高，并且NP组织中的抗DSDNA自身抗体之间存在显着的正相关，这表明局部自身免疫性增加老年人的炎症。在CRS患者中，尤其是在NP中，TNF家族（BAFF）的B细胞激活因子高度升高。 BAFF的这种升高与B细胞/浆细胞数量增加和局部免疫球蛋白的高度相关。这主要是在接受多次鼻窦手术的患者中发现的，这表明顽固形式的疾病形式可能以自身免疫性病因为特征。 CRSWNP中这种局部自身免疫性炎症可能与上皮屏障功能障碍和结果细菌/真菌定殖有关，因为在CRSWNP中，上皮衍生的抗微生物肽，S100A7和S100A8/9的上皮抗微生物肽，S100A7和S100A8/9。 PI发现，老年人进一步降低了S100A8/A9，并且与衰老成反比，这表明老年人中明显的上皮屏障功能障碍。因此，该提议的中心假设是； 1）BAFF激活和扩展B细胞和浆细胞会导致老年人的自身免疫性炎症反应和NP的产生，并且； 2）上皮先天免疫功能与年龄相关的下降导致CRSWNP老年人的持续炎症。这些假设将以三个特定目的进行研究。目的1。为了确定由于明显的B细胞/浆细胞激活和局部自身免疫反应而导致的老年CRS患者是否患有更广泛的顽固性疾病，我们将招募一组对照组（18-49），成熟的成年人（50-64），（50-64），，，50-64），年龄较大的（65-74）和晚期老年（> 75）患有CRSWNP的患者接受了第一次手术（每次n = 15），并比较了BAFF，B细胞，浆细胞，局部免疫球蛋白和NP中NP中局部自身抗体的存在手术时间。我们将前瞻性地遵循他们的临床课程和生物标志物。目的2。要评估BAFF对于NP的形成至关重要，并确定这种情况是否随着年龄的变化而变化，我们将检查成人CRSWNP的鼠模型中的炎症，B细胞激活和局部自身免疫反应（2个月大） ），中年（12个月大），年龄（18个月）。在这种不同年龄的CRSWNP模型中，我们还将用BAFF抑制剂治疗小鼠，并研究BAFF抑制剂对组织病理学反应的影响，B细胞的产生，血浆细胞，IgA/IgG和抗 - 抗菌的产生dsDNA抗体。目的3。为了确定来自老年人的鼻皮细胞是否具有响应各种刺激的宿主防御分子S100蛋白质产生宿主防御分子S100蛋白的能力，我们将获得来自CRSWNP或健康对照的不同年龄组或健康对照的不同年龄组的鼻上皮细胞（n = n =）每个15），并比较有或没有各种刺激的先天能力生产S1008/9。我们将进一步研究用于测试总/磷酸化STAT3缺陷的细胞机制，这是一种信号传导因子，该信号传导因子控制上皮的先天免疫反应，老年人。该建议将提高我们对CRSWNP发病机理中与年龄相关的差异的理解，并将确定老年人中CRSWNP的新治疗靶标。该奖项还将极大地帮助PI获得转化研究能力，并开发技能，以建立新的CRSWNP鼠标模型，以发现新颖的CRSWNP在老年人中最有希望的新型分子靶标。在AIM 1中，选择和招募有CRS的老年患者并前瞻性地跟随他们将大大增强我在老年人的转化和临床科学方面的知识和技能。在AIM 2中，我将在Kim博士的监督下建立一个新的CRSWNP鼠模型。在AIM 3中，我将获得从洪恩受试者（包括空气界面培养技术）培养原发性鼻皮细胞的新技能。我通过该奖项的长期目标是成为老龄化和免疫学领域经验丰富的独立研究者。