The role of surfactant protein-A genetic variant and sex in pathogenesis of neonatal respiratory syncytial virus infection

表面活性蛋白A基因变异和性别在新生儿呼吸道合胞病毒感染发病机制中的作用

• 批准号: 10723170
• 负责人: Chintan K Gandhi
• 金额: $ 17.39万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723170
• 关键词: Adult; Age; Alveolar; Alveolar Macrophages; Antiviral Agents; Antiviral Response; Asthma; Award; Binding; Biological Assay; Biology; Bronchoalveolar Lavage; Cells; Cessation of life; Child; Data; Development; Developmental Biology; Disease; Ensure; Evolution; Experimental Models; Female; Flow Cytometry; Functional disorder; Funding; Future; General Population; Genes; Genetic; Health Care Costs; Host Defense; Human; Imaging Techniques; Immune; Immune system; Immunology; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Integration Host Factors; Knock-out; Knowledge; Life; Lung; Lung diseases; Macrophage; Mediating; Mentorship; Microscopic; Microscopy; Molecular Biology; Monitor; Morbidity - disease rate; Mus; Natural Immunity; Neonatal; Neonatology; Outcome; Pathogenesis; Pathway interactions; Phagocytes; Phase; Phenotype; Physicians; Play; Predisposition; Proteins; Protocols documentation; Pulmonary Surfactant-Associated Protein A; Reporting; Research; Research Personnel; Research Proposals; Respiration; Respiratory Syncytial Virus Infections; Respiratory Therapy; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Risk Factors; Role; Scientist; Severities; Sex Differences; Signal Transduction; Stimulus; Testing; Therapeutic; Therapeutic Effect; Training; Transgenic Organisms; Vaccines; Variant; Viral; Viral Pathogenesis; Virus; Virus Diseases; Wild Type Mouse; adaptive immunity; burden of illness; career development; comparison control; cost estimate; experience; genetic variant; genotypic sex; humanized mouse; improved; in vivo; innovation; insight; interstitial; lung preservation; male; meetings; mortality; mouse model; multidisciplinary; neonatal infection; neonatal mice; neonate; neutrophil; new therapeutic target; novel; novel strategies; pulmonary function; pup; receptor; respiratory; response; sex; skills; spatiotemporal; success; surfactant protein A receptor; therapeutic target; transcriptome; translational scientist; vaccine access; virology; Adult; Age; Alveolar; Alveolar Macrophages; Antiviral Agents; Antiviral Response; Asthma; Award; Binding; Biological Assay; Biology; Bronchoalveolar Lavage; Cells; Cessation of life; Child; Data; Development; Developmental Biology; Disease; Ensure; Evolution; Experimental Models; Female; Flow Cytometry; Functional disorder; Funding; Future; General Population; Genes; Genetic; Health Care Costs; Host Defense; Human; Imaging Techniques; Immune; Immune system; Immunology; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Integration Host Factors; Knock-out; Knowledge; Life; Lung; Lung diseases; Macrophage; Mediating; Mentorship; Microscopic; Microscopy; Molecular Biology; Monitor; Morbidity - disease rate; Mus; Natural Immunity; Neonatal; Neonatology; Outcome; Pathogenesis; Pathway interactions; Phagocytes; Phase; Phenotype; Physicians; Play; Predisposition; Proteins; Protocols documentation; Pulmonary Surfactant-Associated Protein A; Reporting; Research; Research Personnel; Research Proposals; Respiration; Respiratory Syncytial Virus Infections; Respiratory Therapy; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Risk Factors; Role; Scientist; Severities; Sex Differences; Signal Transduction; Stimulus; Testing; Therapeutic; Therapeutic Effect; Training; Transgenic Organisms; Vaccines; Variant; Viral; Viral Pathogenesis; Virus; Virus Diseases; Wild Type Mouse; adaptive immunity; burden of illness; career development; comparison control; cost estimate; experience; genetic variant; genotypic sex; humanized mouse; improved; in vivo; innovation; insight; interstitial; lung preservation; male; meetings; mortality; mouse model; multidisciplinary; neonatal infection; neonatal mice; neonate; neutrophil; new therapeutic target; novel; novel strategies; pulmonary function; pup; receptor; respiratory; response; sex; skills; spatiotemporal; success; surfactant protein A receptor; therapeutic target; transcriptome; translational scientist; vaccine access; virology

Project summary: This K08 proposal describes a 5-year research and training plan that will facilitate the transition of Chintan Gandhi, MD to an independent researcher in the field of lung innate immunity and host defense. Dr. Gandhi is establishing himself as a basic and translational researcher focusing on innate immune responses to respiratory infections with a focus on the respiratory syncytial virus (RSV). Although RSV is the leading cause of mortality due to viral respiratory illnesses in children worldwide, there are no virus-specific treatments or vaccines currently available. This is partly due to an incomplete understanding of the interaction between the virus and the immature host immune system. Age at initial infection and male sex are independent risk factors for RSV severity. Surfactant protein A (SP-A), an innate immune protein, regulates phagocytic and inflammatory functions of alveolar macrophages (AMs) through the surfactant protein-A-receptor 210 (SP- R210). SP-A genetic variants and low levels of SP-A are associated with RSV severity. Dr. Gandhi reported associations of young age and the 1A0 variant of SFTPA2 (SFTPA2-1A0) with RSV severity in children. The focus of this proposal is to investigate the underlying mechanisms of those associations using a humanized transgenic neonatal mouse model of RSV carrying the SFTPA2-1A0 variant. The central hypothesis is that SP- A genetic variants and male sex converge to dysregulate the SP-A/SP-R210 pathway in neonatal AMs leading to delayed RSV clearance and excessive inflammation. The central hypothesis will be tested via the following Specific Aims: 1) determine how SFTPA2-1A0 regulates in vivo AM differential responses to RSV in male and female pups, and 2) elucidate mechanisms of the SFTPA2-1A0 mediated dysfunction of SP-A/SP-R210 pathway in RSV clearance and define in vivo therapeutic effects of exogenous SP-A in neonatal RSV infection. These studies will yield important information about the SP-A/SP-R210 signaling as a novel pathway in RSV severity and will also determine if SP-A, its receptor, SP-R210, or the modulation of the SP-A/SP-R210 pathway may be future therapeutic targets for RSV infection. During the award period, Dr. Gandhi will continue to develop his expertise in immunology, molecular biology, and genetics. In addition, Dr. Gandhi will develop skills in flow cytometry and microscopic approaches to study viral dynamics. A multidisciplinary mentorship team has been assembled to ensure the success of this project, and includes expertise in virus biology, pathogenesis, and development of novel antiviral agents (Dr. Lukacher); lung cell purification, culture protocols, and advanced life imaging techniques (Dr. Chroneos); and mechanisms of sex differences in neonatal pulmonary diseases (Dr. Lingappan). The mentorship team will guide Dr. Gandhi in meeting his training objectives through direct research experience, formal didactics, and participation in career development opportunities. The research described in this proposal is innovative and will be a substantive addition to the knowledge gap and will help Dr. Gandhi to become an independent R01-funded investigator.

项目摘要：该K08提案描述了一项为期5年的研究和培训计划，该计划将促进 医学博士Chintan Gandhi过渡到肺部免疫和宿主领域的独立研究员 防御。甘地博士正在将自己确立为一位专注于先天免疫的基本和转化研究员 对呼吸道感染的反应，重点是呼吸道合胞病毒（RSV）。虽然RSV是 全球儿童病毒呼吸道疾病引起的死亡的主要原因，没有病毒特异性 当前可用的治疗或疫苗。这部分是由于对互动的不完全理解 在病毒和未成熟的宿主免疫系统之间。初期感染和男性的年龄是独立的 RSV严重程度的风险因素。表面活性剂蛋白A（SP-A），一种先天免疫蛋白，调节吞噬细胞和 肺泡巨噬细胞（AMS）通过表面活性剂蛋白A受体210（SP-）的炎症功能 R210）。 SP-A遗传变异和低水平的SP-A与RSV严重程度有关。甘地博士报道 SFTPA2（SFTPA2-1A0）与儿童的RSV严重程度的SFTPA2（SFTPA2-1A0）的1A0变体的关联。这 该建议的重点是使用人源化研究这些关联的基本机制 带有SFTPA2-1A0变体的RSV的转基因新生小鼠模型。中心假设是 一种遗传变异和男性会融合到新生儿AMS中的SP-A/SP-R210途径失调 延迟RSV清除和过度炎症。中心假设将通过以下测试 具体目的：1）确定SFTPA2-1A0如何调节男性和RSV的体内差异反应 女幼崽和2）SFTPA2-1A0介导的SP-A/SP-R210功能障碍的机制 RSV清除率的途径并定义了新生儿RSV感染中外源性SPA的体内治疗作用。 这些研究将产生有关SP-A/SP-R210信号作为RSV中新途径的重要信息 严重程度，还将确定SP-A，其受体，SP-R210还是SP-A/SP-R210的调制 途径可能是RSV感染的未来治疗靶标。在颁奖期间，甘地博士将继续 发展他在免疫学，分子生物学和遗传学方面的专业知识。此外，甘地博士将发展 流式细胞仪和显微镜方法的技能研究病毒动力学。多学科指导 团队已经组装以确保该项目的成功，并包括病毒生物学专业知识， 发病机理和新型抗病毒剂的发展（Lukacher博士）；肺细胞纯化，培养 协议和高级生活成像技术（Chroneos博士）；性别差异的机制 新生儿肺部疾病（Lingappan博士）。指导团队将指导甘地博士见面 通过直接研究经验，正式教学和参与职业培训目标 发展机会。该提案中描述的研究具有创新性，将是实质性的 除了知识差距外，还将帮助甘地博士成为一名独立的R01资助的研究者。