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

• 批准号: 10393663
• 负责人: William Damsky
• 金额: $ 17.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10393663
• 关键词: Adverse effects; Affect; African American population; Archives; 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; Immune; Immunobiology; Immunohistochemistry; Immunologics; Immunology; In Situ Hybridization; Individual; Inflammation; Inflammatory; Intercellular Fluid; Interferon Type II; Interferon-alpha; Interferons; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-18; Interleukin-2; Interleukin-4; Interleukin-6; JAK1 gene; Janus kinase; Laboratories; Lead; Leadership; Lesion; Ligands; Lung; 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; Sum; T-Lymphocyte; TNF gene; Testing; Tissues; Training; Work; autoreactivity; base; biobank; body system; career development; cell type; chemokine; cytokine; design; effective therapy; efficacy evaluation; experience; experimental study; improved; inhibitor; interest; kinase inhibitor; lymph nodes; macrophage; medical schools; molecular targeted therapies; monocyte; mortality; novel strategies; 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; treatment effect

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 本K 08申请中描述的研究和职业发展活动旨在使William博士 Damsky，首席研究员，在人类转化和基础免疫学方面拥有经验和专业知识 成为这些领域的独立调查员。研究提案的重点是结节病， 一种自发性的炎症，特征是在受影响的组织中形成肉芽肿。结节病 导致显著的发病率和死亡率，并对美国的非洲裔美国人造成不良影响。 目前对结节病的治疗并不令人满意。我们已经发现Janus激酶（JAK）抑制剂可以用于 在其他药物治疗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。基于我们的初步研究，我们假设JAK抑制剂通过阻断 由致病性CD 4 + T细胞产生的特异性JAK依赖性细胞因子的活性， 巨噬细胞在这个建议中，我们描述了我们将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-细胞相互作用组图谱，以解卷积驱动肉芽肿的信号 形成结节病。将特别关注JAK依赖性细胞因子。接下来，使用生物储存库 10例全身性结节病患者在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抑制的作用机制， 疾病和评估在基线和对JAK抑制剂的应答时免疫学特征的异质性。 我们还将使用蛋白质组学方法来分析10名患者在治疗前和治疗期间的血浆细胞因子水平。 JAK抑制剂治疗，以确定反应的潜在生物标志物和治疗对炎症的影响， 系统层面。最后，我们将对来自多个器官（淋巴）的结节病组织进行空间转录组学研究。 淋巴结和肺），以评估我们的假设，即核心细胞因子信号驱动肉芽肿形成， 结节病在不同的器官中很大程度上是保守的。总之，本提案的研究部分将 评估一种有前途的新的治疗方法的分子机制， 目前缺乏经批准的疗法。该提案还将支持职业发展时期， 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 耶鲁医学院免疫生物学系的Flavell博士说。这种高度协作和支持 研究环境与定向的额外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力将使我能够 作为一名医生科学家，我成功地实现了研究独立，并开设了自己的实验室， 使用基础和转化免疫学方法研究炎性疾病，包括结节病。