Determining the molecular basis for different rates of T1D progression

确定不同 T1D 进展速度的分子基础

• 批准号: 8837241
• 负责人: Peter S Linsley
• 金额: $ 109.6万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837241
• 关键词: Address; Adverse effects; Autoimmune Diseases; Beta Cell; Biological Markers; Biological Preservation; Blood specimen; C-Peptide; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Clinical; Combined Modality Therapy; Control Groups; Data; Diagnosis; Disease; Disease remission; Effectiveness; Flow Cytometry; Funding; Gene Expression Profile; Goals; Health; Heterogeneity; Immune; Immune Tolerance; Immunologics; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Laboratories; Lead; MS4A1 gene; Measures; Molecular; Molecular Profiling; Monitor; Muromonab-CD3; Natural History; Natural Killer Cells; Newly Diagnosed; Patient Selection; Patients; Personal Satisfaction; Phenotype; Placebos; RNA Sequence Analysis; Randomized; Request for Proposals; Sampling; Systems Biology; T-Lymphocyte; Technology; Therapeutic; Time; Whole Blood; alefacept; base; cell type; clinical Diagnosis; clinical effect; cost; cost effectiveness; disease natural history; falls; improved; insight; molecular marker; phase 2 study; response; rituximab; success; transcription factor

DESCRIPTION (provided by applicant): Disease-modifying therapies with distinct mechanisms of action are now available to treat autoimmune diseases. Several agents have shown the ability to delay onset of Type I Diabetes (T1D), but only in a fraction of patients and for a limited period of time. Why these disparate agents show such similar clinical effects remains unknown, but their limited effectiveness, high cost and potential for undesirable side effects have limited their usefulness in T1D. By better selecting patients for treatment, the likelihood of treatment success, patient well-being, and cost-effectiveness may improve. We are using cutting edge systems biology approaches to identify cellular and molecular markers characterizing the preservation of beta cell function in newly diagnosed subjects with T1D (non-progressors). In preliminary studies, we used RNA sequencing analysis (RNAseq) to identify a gene expression signature of EOMES-positive cells in whole blood samples from non-progressors after teplizumab treatment. With the current proposal, we request funding to expand our initial studies by pursuing three molecular profiling-related approaches: Identify unique and shared molecular/cellular signatures distinguishing T1D non-progressors from progressors following treatment. We will use RNAseq analysis to identify whole blood molecular signatures in subjects treated with several agents that protect beta cell function, including abatacept, rituximab, and alefacept. Identify molecular/cellular signatures distinguishing T1D non-progressors from progressors during the natural history of T1D after diagnosis. We will use RNAseq analysis to identify signatures in whole blood of T1D subjects that naturally show preserved beta cell function, even without treatment. Signatures from the first two approaches will be compared with our teplizumab signature to determine whether each is unique or treatment-specific. Identify cell types accumulating in non-progressor teplizumab-treated patients from the AbATE study and generate hypotheses as to their function. We will perform flow cytometry and single cell transcriptome profiling studies to characterize the EOMES-positive cells identified in our preliminary studies. Together, we expect these studies to yield improved understanding of immune aspects of beta cell preservation in T1D. We also anticipate identifying new biomarkers, better strategies for patient selection and more rational combination therapies for T1D.

描述（由申请人提供）：具有不同作用机制的疾病修饰疗法现在可用于治疗自身免疫性疾病。几种药物已经显示出延迟I型糖尿病（T1 D）发作的能力，但仅在一小部分患者中并且在有限的时间段内。为什么这些不同的药物显示出如此相似的临床效果仍然未知，但它们有限的有效性、高成本和潜在的不良副作用限制了它们在T1 D中的有用性。通过更好地选择患者进行治疗，治疗成功的可能性，患者福祉和成本效益可能会提高。我们正在使用最先进的系统生物学方法来识别表征新诊断的T1 D受试者（非进展者）中β细胞功能保留的细胞和分子标志物。在初步研究中，我们使用RNA测序分析（RNAseq）来鉴定teplizumab治疗后非进展者全血样本中EOMES阳性细胞的基因表达特征。根据目前的提议，我们要求通过三种分子分析相关方法来扩大我们的初步研究：确定独特和共享的分子/细胞特征，将T1 D非进展者与治疗后的进展者区分开来。我们将使用RNAseq分析来识别接受多种保护β细胞功能的药物治疗的受试者的全血分子特征，包括阿巴西普，利妥昔单抗和阿法西普。确定在诊断后的T1 D自然史期间区分T1 D非进展者与进展者的分子/细胞特征。我们将使用RNAseq分析来识别T1 D受试者全血中的特征，这些特征即使在没有治疗的情况下也能自然地显示出保留的β细胞功能。前两种方法的特征将与我们的teplizumab特征进行比较，以确定每种方法是否是独特的或治疗特异性的。识别AbATE研究中接受替普利单抗治疗的非进展患者中蓄积的细胞类型，并对其功能进行假设。我们将进行流式细胞术和单细胞转录组分析研究，以表征我们初步研究中鉴定的EOMES阳性细胞。总之，我们希望这些研究能够提高对T1 D中β细胞保存的免疫方面的理解。我们还期待发现新的生物标志物，更好的患者选择策略和更合理的T1 D联合治疗。