Delineation of the immunobiology of sarcoidosis and characterization of the effects of Janus kinase inhibition

结节病免疫生物学的描述和 Janus 激酶抑制作用的表征

基本信息

批准号：
10652267
负责人：
William Damsky
金额：
$ 17.23万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652267
关键词：
Adverse effects Affect African American population Area Attention Automobile Driving Biopsy Blood specimen CCL4 gene CD4 Positive T Lymphocytes Case Study Cells Characteristics Chronic Chronic Disease Clinical Clinical Trials Cutaneous Sarcoidosis Cytokine Signaling Development Disease Endothelial Cells Enrollment Environment FDA approved Fibroblasts Freezing Future Granulocyte-Macrophage Colony-Stimulating Factor Granuloma Granulomatous disease Heterogeneity Histologic Human IL17 gene IL18 gene Immune Immunobiology Immunohistochemistry Immunologics Immunology In Situ Hybridization Individual Inflammation Inflammatory Intercellular Fluid Interferon Type II Interferon alpha Interferons Interleukin-12 Interleukin-13 Interleukin-2 Interleukin-4 Interleukin-6 JAK1 gene Janus kinase Laboratories Leadership Ligands Lung Macrophage Macrophage Activation Maps Methotrexate Molecular Molecular Target Morbidity - disease rate Organ Pathogenesis Pathogenicity Pathology Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Physicians Plasma Prednisone Principal Investigator Production Proteins Proteomics RANTES RNA Reporting Research Research Personnel Research Proposals STAT protein Sarcoidosis Scientist Signal Transduction Site Skin Specimen T-Lymphocyte TNF gene Testing Tissues Training Work autoreactivity biobank body system career development cell type chemokine comparison control cytokine design effective therapy efficacy evaluation experience experimental study improved inhibitor interest kinase inhibitor lymph nodes medical schools molecular targeted therapies monocyte mortality novel strategies novel therapeutic intervention open label potential biomarker predicting response receptor recruit repository response response biomarker single-cell RNA sequencing systemic inflammatory response therapeutic target transcriptome transcriptome sequencing transcriptomics translational immunology treatment effect

项目摘要

Project Summary The studies and career development activities described in this K08 application are designed to equip Dr. William Damsky, the Principal Investigator, with experience and expertise in human translational and basic immunology in order to become in independent investigator in these areas. The focus of the research proposal is sarcoidosis, an idiopathic inflammatory disorder characterized by the formation of granulomas in affected tissues. Sarcoidosis causes significant morbidity and mortality and disproportionally affects African Americans in the U.S. Treatments for sarcoidosis are currently unsatisfactory. We have discovered that Janus kinase (JAK) inhibitors can be used to treat sarcoidosis in contexts where other medications have failed and are currently performing a clinical trial to evaluate this further. Based on our preliminary studies, we hypothesize that JAK inhibitors work by blocking the activity of specific JAK-dependent cytokines produced by pathogenic CD4+ T cells that in turn activate macrophages. In this proposal, we describe how we will use cutaneous sarcoidosis biopsies and single cell RNA sequencing to create a receptor-ligand based cell-cell interactome map to deconvolute signals driving granuloma formation in sarcoidosis. Special attention will be given to JAK-dependent cytokines. Next, using a biorepository of skin and blood samples from 10 patients with systemic sarcoidosis before and during treatment with a Janus kinase inhibitor, we will use multiple approaches to determine the mechanism of action of JAK inhibition in this disease and evaluate heterogeneity in immunologic characteristics at baseline and in response to a JAK inhibitor. We will also use proteomic approaches to profile plasma cytokine levels in the 10 patients before and during JAK inhibitor treatment to identify potential biomarkers of response and effects of treatment on inflammation at a systemic level. Last, we will perform spatial transcriptomics on sarcoidosis tissues from multiple organs (lymph nodes and lungs) to evaluate our hypothesis that core cytokine signals that drive granuloma formation in sarcoidosis are largely conserved among different organs. In summary, the research portion of this proposal will evaluate molecular mechanisms for a promising new treatment approach for a disease in which effective approved therapies are currently lacking. The proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Richard Flavell in the Department of Immunobiology at Yale School of Medicine. This highly collaborative and supportive research environment combined with directed additional career development activities focused on computational approaches, quantitative pathology, spatial transcriptomics, and academic leadership will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study inflammatory disorders including sarcoidosis.

项目概要本 K08 申请中描述的学习和职业发展活动旨在装备 William 博士 Damsky，首席研究员，在人类翻译和基础免疫学方面拥有丰富的经验和专业知识以便成为这些领域的独立调查员。该研究提案的重点是结节病，一种特发性炎症性疾病，其特征是受影响组织中形成肉芽肿。结节病导致显着的发病率和死亡率，并对美国的非裔美国人产生不成比例的影响目前对于结节病的治疗效果并不令人满意。我们发现 Janus 激酶 (JAK) 抑制剂可用于在其他药物失败且目前正在进行临床试验的情况下治疗结节病进一步评估这一点。根据我们的初步研究，我们假设 JAK 抑制剂通过阻断致病性 CD4+ T 细胞产生的特定 JAK 依赖性细胞因子的活性，进而激活巨噬细胞。在本提案中，我们描述了如何使用皮肤结节病活检和单细胞 RNA 测序以创建基于受体-配体的细胞-细胞相互作用图谱，以解卷积驱动肉芽肿的信号结节病的形成。将特别关注 JAK 依赖性细胞因子。接下来，使用生物样本库 10 名系统性结节病患者在使用 Janus 治疗前和治疗期间的皮肤和血液样本激酶抑制剂，我们将使用多种方法来确定 JAK 抑制在此方面的作用机制疾病并评估基线免疫特征和对 JAK 抑制剂的反应的异质性。我们还将使用蛋白质组学方法来分析 10 名患者术前和术中的血浆细胞因子水平。 JAK 抑制剂治疗可识别潜在的反应生物标志物以及治疗对炎症的影响系统层面。最后，我们将对来自多个器官（淋巴淋巴结和肺）来评估我们的假设，即驱动肉芽肿形成的核心细胞因子信号结节病在不同器官之间很大程度上具有保守性。总之，该提案的研究部分将评估一种有前途的新治疗方法的分子机制，该方法可有效治疗疾病目前缺乏批准的疗法。该提案还将支持一段时期的职业发展我将在理查德博士的实验室接受基础和转化免疫学的额外培训 Flavell 是耶鲁大学医学院免疫生物学系的教授。这种高度协作和支持的研究环境与以计算为重点的定向额外职业发展活动相结合方法、定量病理学、空间转录组学和学术领导力将使我能够作为一名医师科学家成功实现了研究独立性，并开设了自己的实验室，这样我就可以使用基本和转化免疫学方法来研究包括结节病在内的炎症性疾病。