Molecular and cellular analysis of host response to Cocci

宿主对球菌反应的分子和细胞分析

• 批准号: 10364968
• 负责人: Anita Sil
• 金额: $ 38.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364968
• 关键词: Antibodies; Area; Bacteriophages; Biopsy Specimen; Blood; Blood specimen; Bone Marrow; California; Cancer Patient; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coccidioides; Coccidioides immitis; Coccidioidomycosis; Collaborations; Complex; Cytometry; Data; Development; Diagnostic; Disease; Disease Outcome; Elements; Epitope Mapping; Etiology; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Granulomatous; Human; Immune; Immune response; In Vitro; Infection; Infrastructure; Learning; Letters; Libraries; Lung; Lung nodule; Meningitis; Modeling; Molecular; Molecular Profiling; Mus; Neurologist; Nodule; Pathology; Pathway interactions; Patients; Peptides; Phage Display; Population; Proteome; Reaction; Research Personnel; Resolution; Resources; Sampling; Serology; Serum; Structure of parenchyma of lung; Technology; Testing; Therapeutic; Tumor Tissue; Vaccine Design; Variant; Virulence; adaptive immune response; base; cell type; chronic infection; clinical diagnostics; community acquired pneumonia; desert fever; diagnostic biomarker; immunogenic; infectious meningitis; insight; interest; macrophage; microbial; microbial genome; mutant; next generation; pathogen; pathogenic fungus; response; single-cell RNA sequencing; success; targeted treatment; transcriptomics

Project 2 Molecular and Cellular Analysis of Host Response to Coccidioides Project Summary In project 2, we will apply sophisticated technologies to interrogate the host response to Coccidioides. Coccidioides infections cause a broad range of disease outcomes ranging from subclinical infection to a community-acquired pneumonia, to disseminated central nervous system disease. It has been postulated that variation in the host response, including potential differences in innate and/or adaptive immune responses, contributes to the spectrum of disease manifestations. The long-term goal of Project 2 is to apply transcriptomics, mass cytometry, single-cell RNAseq, and phage display to analyze the molecular and cellular response to Coccidioides infection using both in vitro infection models and patient samples. Our goal is to examine the host response in three critical areas that benefit from the expertise and resources available to the investigators. We will establish a baseline profile of the macrophage response to Coccidioides by comparing the transcriptional profile of these host cells to infection with either wild-type or avirulent Coccidioides strains (the latter generated in the CRISPR and Virulence Core). To characterize and compare the human response to chronic infection we will use mass cytometry and single-cell RNAseq to interrogate lung nodules from Valley Fever patients in the endemic region of California. These studies would be challenging for most investigators and are made possible here by the sophisticated infrastructure available at the UCSF CoLabs (see letter of support). Additionally, we will take advantage of a rich set of clinical samples (from UC Davis, Project 3 and Clinical and Diagnostics Core) to profile cerebrospinal fluid (CSF) from patients with disseminated coccidioidal meningitis. Additionally, to determine which elements of the host response can be utilized for diagnostic applications, we will use high-resolution epitope-mapping technology to identify the most immunogenic regions of the Coccidioides proteome. Notably this project will draw new investigators into the coccidioidomycosis field. Taken together, we hope to amplify our understanding of the molecular and cellular constituents of the host response to Coccidioides infection, providing a critical foundation for the development of future diagnostics and therapeutics.

项目 2 宿主对球孢子菌反应的分子和细胞分析 项目概要 在项目 2 中，我们将应用复杂的技术来询问宿主对球孢子菌的反应。 球孢子菌感染可引起多种疾病结果，从亚临床感染到严重感染 社区获得性肺炎，传播性中枢神经系统疾病。据推测 宿主反应的变化，包括先天性和/或适应性免疫反应的潜在差异， 有助于疾病表现的范围。项目2的长期目标是应用转录组学， 质谱流式分析、单细胞 RNAseq 和噬菌体展示来分析分子和细胞反应 使用体外感染模型和患者样本进行球孢子菌感染。 我们的目标是检查东道主在三个关键领域的反应，这些领域受益于专业知识和 调查人员可用的资源。我们将建立巨噬细胞反应的基线概况 通过将这些宿主细胞的转录谱与野生型或野生型球孢子菌感染进行比较 无毒力的球孢子菌菌株（后者在 CRISPR 和毒力核心中生成）。表征和 比较人类对慢性感染的反应，我们将使用质谱流式细胞术和单细胞 RNAseq 来 研究加利福尼亚州谷热流行区患者的肺结节。这些研究将是 对大多数调查人员来说具有挑战性，而这里的复杂基础设施使之成为可能 UCSF CoLabs（参见支持信）。此外，我们将利用丰富的临床样本 （来自加州大学戴维斯分校，项目 3 和临床和诊断核心）分析患者的脑脊液 (CSF) 患有播散性球孢子菌脑膜炎。此外，为了确定宿主响应的哪些元素可以 用于诊断应用时，我们将使用高分辨率表位作图技术来识别 球孢子菌蛋白质组中最具免疫原性的区域。值得注意的是，该项目将吸引新的研究人员 球孢子菌病领域。总而言之，我们希望加深我们对分子和细胞的理解 宿主对球孢子菌感染反应的组成部分，为球孢子菌感染的发展提供了重要基础 未来的诊断和治疗。