Determining the molecular basis for different rates of T1D progression

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。一些药物已经显示出延迟1型糖尿病（T1D）发病的能力，但仅对一小部分患者和有限的时间有效。为什么这些不同的药物表现出如此相似的临床效果尚不清楚，但它们有限的疗效、高昂的成本和潜在的不良副作用限制了它们在T1D中的应用。通过更好地选择患者进行治疗，治疗成功的可能性，患者的福祉和成本效益可能会提高。我们正在使用尖端的系统生物学方法来鉴定新诊断的T1D（非进展者）受试者中β细胞功能保存的细胞和分子标记物。在初步研究中，我们使用RNA测序分析（RNAseq）鉴定了替普利单抗治疗后非进展患者全血样本中emes阳性细胞的基因表达特征。根据目前的提案，我们请求资金来扩展我们的初始研究，通过追求三种与分子谱相关的方法：识别治疗后区分T1D非进展者和进展者的独特和共享的分子/细胞特征。我们将使用RNAseq分析来鉴定使用几种保护β细胞功能的药物治疗的受试者的全血分子特征，这些药物包括阿巴接受普、利妥昔单抗和阿法塞普。在诊断后的T1D自然病程中，识别区分T1D非进展者和进展者的分子/细胞特征。我们将使用RNAseq分析来识别T1D受试者全血中自然保存的β细胞功能的特征，即使没有治疗。前两种方法的特征将与我们的teplizumab特征进行比较，以确定每种方法是独特的还是治疗特异性的。从AbATE研究中确定非进展性替普利单抗治疗患者中积累的细胞类型，并对其功能产生假设。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emes阳性细胞。总之，我们期望这些研究能够提高对T1D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T1D联合治疗。

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.