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.

项目摘要该K08应用程序中描述的研究和职业发展活动旨在为威廉博士配备。首席研究员达姆斯基（Damsky）具有人类翻译和基本免疫学方面的经验和专业知识为了成为这些领域的独立研究者。研究建议的重点是结节病，一种特发性炎症性疾病，其特征是受影响组织中肉芽肿的形成。结节病引起严重的发病率和死亡率，并对美国治疗中的非洲裔美国人产生不成比例的影响对于结节病，目前不令人满意。我们发现可以使用Janus激酶（JAK）抑制剂在其他药物失败并目前正在进行临床试验的情况下治疗结节病进一步评估。根据我们的初步研究，我们假设JAK抑制剂通过阻止致病性CD4+ T细胞产生的特定JAK依赖性细胞因子的活性，后者又激活巨噬细胞。在此提案中，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 - 细胞相互作用组图，以驱动颗粒状瘤结节病的形成。将特别注意依赖JAK的细胞因子。接下来，使用生物座 janus治疗前后，10例全身性结节病患者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抑制作用的作用机理疾病并评估基线和响应JAK抑制剂的免疫特征的异质性。我们还将使用蛋白质组学方法在10例之前和期间介绍10例患者的血浆细胞因子水平 JAK抑制剂治疗以确定治疗对炎症的反应和影响的潜在生物标志物系统水平。最后，我们将对来自多个器官的结节病组织进行空间转录组学（淋巴节点和肺）评估我们的假设，即驱动肉芽肿形成的核心细胞因子信号在不同的器官中，结节病在很大程度上是保守的。总而言之，该提案的研究部分将评估分子机制的有效疾病的新治疗方法，其中有效目前缺乏批准的疗法。该提案还将支持在职业发展期间的一段我将在理查德博士的实验室中获得基本和转化免疫学的其他培训耶鲁大学医学院免疫生物学系的Flavell。这种高度协作和支持研究环境与指导的其他职业发展活动相结合，重点是计算方法，定量病理学，空间转录组学和学术领导才能使我能够成功地作为医师科学家实现研究独立性，并开设自己的实验室，以便我可以使用基本和转化的免疫学方法研究包括结节病在内的炎症性疾病。