Significance Circulating Semaphorin 7a+ve Cells in Pulmonary Sarcoidosis

循环信号蛋白 7a ve 细胞在肺结节病中的意义

基本信息

批准号：
8464240
负责人：
Erica L Herzog
金额：
$ 15.84万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464240
关键词：
Affect Alveolar Macrophages Antigen Presentation Automobile Driving Biological Biological Markers Blood Blood Circulation Blood specimen CD4 Positive T Lymphocytes Cell Culture Techniques Cells Cessation of life Characteristics Chronic Clinical Clinical Paths Complex Confocal Microscopy Cultured Cells Disease Disease Progression Environment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Flow Cytometry Genes Genetic Goals Grant Granuloma Hematopoietic Immunologic Factors Immunosuppressive Agents Indolent Inflammation Inflammatory Investigation Lead Link Lung Lung diseases Measurement Mediator of activation protein Membrane Proteins Mus Nature Newly Diagnosed Pathogenesis Pathology Patients Phenotype Population Production Progressive Disease Proteins Pulmonary Sarcoidosis Recruitment Activity Regulatory T-Lymphocyte Respiratory physiology Sampling Sarcoidosis Semaphorins Testing Tissues United States National Institutes of Health alpha 1-Antitrypsin Deficiency biobank chemokine cohort cytokine disease phenotype insight macrophage monocyte neuronal guidance novel novel therapeutics peripheral blood repaired

项目摘要

DESCRIPTION (provided by applicant): Sarcoidosis is a chronic inflammatory disease that often results in progressive, untreatable pathology. It likely results from complex interactions between unidentified genetic, infectious, and/or environmental factors that combine to induce ongoing granuloma formation in affected tissues. These granulomas contain increased numbers of monocytes and CD4+ T cells and are accompanied by increased proinflammatory cytokines and chemokines, as well as by abnormalities in regulatory T cells (Tregs) which normally function to control inflammation. Little is known about how these factors lead to phenotypic differences in disease activity. Thus, while many patients with sarcoidosis will stabilize and in some cases even remit, approximately 20% of patients will develop progressive disease that in some cases results in death. Until we understand this disease better, there is little hope for predicting the clinical course and finding new therapies. We have recently found that the blood of patients with sarcoidosis contains several unique cell populations with potential import in disease pathogenesis. We have found that sarcoid patients show increased numbers of circulating fibrocytes, and that (unlike normal controls) these cells secrete increased quantities of proinflammatory cytokines. We have also found that the blood of sarcoid patients contains a unique Treg population that expresses Semaphorin 7a, and that these cells appear to stimulate exaggerated fibrocyte outgrowth and cytokine secretion. Curiously, both fibrocytes and Sema 7a+ Tregs are most elevated in those sarcoid patients with severe or progressive disease and as such may be related to disease phenotype. This grant tests the hypothesis that fibrocytes and/or Sema 7a+ Tregs function as biomarkers of disease progression in patients with newly diagnosed pulmonary sarcoidosis. In aim 1 we will recruit and characterize a cohort of sarcoid patients (and controls) to create a biorepository for the proposed studies. In aims 2 and 3 we will quantify circulating fibrocytes and Sema 7a+ Tregs and assess their ability to predict disease progression in the subjects recruited in aim 1. Mechanistic studies will be performed to determine the nature of the fibrocyte-Treg interactions. It is hoped that these studies will deepen our understanding of disease progression in patients with sarcoidosis and lead to new insight that could lead to novel therapeutic options.

描述（由申请人提供）：结节病是一种慢性炎性疾病，通常会导致进行性，不可治疗的病理。它可能是由于未鉴定的遗传，传染和/或环境因素之间的复杂相互作用而引起的，这些因素结合起来诱导受影响组织中持续的肉芽肿形成。这些颗粒含有增加的单核细胞和CD4+ T细胞的数量，并伴随着促炎性细胞因子和趋化因子的增加，以及调节性T细胞（Tregs）的异常，通常可以控制炎症。这些因素如何导致疾病活动的表型差异知之甚少。因此，尽管许多结节病的患者将稳定，在某些情况下甚至使大约20％的患者患有进行性疾病，在某些情况下会导致死亡。除非我们更好地理解这种疾病，否则对临床过程和发现几乎没有希望新疗法。我们最近发现，结节病患者的血液包含几个独特的细胞群体，具有潜在的进口疾病发病机理。我们发现，肌体患者显示出循环纤维细胞的数量增加，并且（与正常对照不同）这些细胞分泌促炎性细胞因子的数量增加。我们还发现，结节患者的血液中包含一种独特的Treg种群，表达了信号素7a，并且这些细胞似乎刺激了夸张的纤维细胞生长和细胞因子分泌。奇怪的是，在那些患有严重或进行性疾病的曲折患者中，纤维细胞和SEMA 7A+ Treg均升高，因此可能与疾病表型有关。该赠款检验了以下假设：纤维细胞和/或SEMA 7A+ Tregs在新诊断的肺结节病患者中起疾病进展的生物标志物。在AIM 1中，我们将招募和表征一组结节患者（和对照组），以创建拟议研究的生物措施。在目标2和3中，我们将量化循环纤维细胞和SEMA 7A+ Tregs，并评估其预测目标1中招募的受试者中疾病进展的能力。将进行机械研究以确定纤维细胞 - Treg相互作用的性质。希望这些研究能够加深我们对结节病患者疾病进展的理解，并带来新的见解，这可能导致新的治疗选择。