Whole blood gene expression to identify biomarkers of disease risk, progression and response to therapy in Type 1 diabetes

全血基因表达可识别 1 型糖尿病疾病风险、进展和治疗反应的生物标志物

基本信息

批准号：
9918349
负责人：
CHARLES GARRISON FATHMAN
金额：
$ 43.3万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-10 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918349
关键词：
Abate Address Agreement Ancillary Study Autoantibodies Beta Cell Biological Assay Biological Markers Blood Cells CD3 Antigens CTLA4-Ig Cell physiology Clinical Data Development Diabetes Mellitus Disease Disease Progression Disease susceptibility Enrollment Epigenetic Process Expression Profiling Family Family history of First Degree Relative Florida Foundations Funding Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Gold Grant Hyperglycemia Individual Institutional Review Boards Insulin-Dependent Diabetes Mellitus Interferons Intervention Intervention Trial Lead Letters National Institute of Allergy and Infectious Disease Pathogenesis Pathway interactions Patient Selection Patients Pattern Pharmaceutical Preparations Phenotype Prediabetes syndrome Predisposition Prevention Prevention trial Process RNA Research Risk Sampling Serum Testing Therapeutic Intervention Time Universities Whole Blood Work adaptive immune response base disorder prevention disorder risk drug efficacy high risk population nano-string novel peripheral blood point of care prognostic progression marker repository responders and non-responders response response biomarker seroconversion successful intervention targeted treatment therapy development tool transcriptome sequencing

项目摘要

Summary In this grant, we propose to perform gene expression analysis on peripheral blood cells (PBC) of auto-antibody negative first degree relatives of T1D patients (AA- FDRs) and AA+ FDRs who have either progressed (progressors) or not progressed to hyperglycemia (non- progressors), compared to healthy non-T1D related controls. We will also perform gene expression analysis on PBCs of patients enrolled in the TrialNet Abatacept (CTLA4-Ig) New Onset Study (TN-09). The proposed studies will confirm and extend our work on the identification of whole blood biomarkers of disease susceptibility and disease progression in T1D, and initiate our studies on biomarkers of response to therapy. Preliminary data generated under funding from the JDRF suggests that the PBC gene expression profiles of T1D and T1D-related individuals are more similar to each other than to healthy normal non-diabetes-related controls; that is, there is a prodromal gene expression signature that can identify disease risk in the PBCs of AA- FDRs of T1D patients who show no clinical signs of disease. Based on these preliminary data, we hypothesize that families of T1D patients, all have an environmentally-driven, epigenetically-controlled gene expression signature of risk that can be seen in peripheral blood. We identified a subset of AA- FDRs that had elevated levels of interferon-induced gene expression in their PBCs. These individuals also expressed a gene expression signature that was more similar to AA+ FDRs who progressed to hyperglycemia than to AA+ FDRs who did not progress, or to other AA- FDRs, and to controls, suggesting that whole blood gene expression biomarkers could be used to identify individuals who will progress to hyperglycemia prior to seroconversion. In patients who seroconverted (AA+), we found that gene expression was most changed during the early stages of disease (>3 years before the onset of hyperglycemia) in progressors compared to non-progressors. This indicates that we might be able to identify biomarkers that not only distinguish AA+ progressors from AA+ non-progressors, but also predict the rate of disease progression. Finally, studies have shown that PBC gene expression signatures differ in recent onset hyperglycemic patients that responded to anti-CD3 therapy compared to those who did not respond (AbATE trial). We hypothesize that we may also see a difference in gene expression in patients who respond to CTA4-Ig (Abatacept) compared to those who do not respond, 3 months after the initiation of therapy (TN-09). If non-responders could be identified early, this would allow time for other therapies to be tested before total loss of beta cell mass/function occurs. Three specific aims are proposed. The first specific aim is to validate the prodromal gene expression pattern seen in diabetes related AA- individuals. The second specific aim is to identify both a PBC gene expression signature of T1D disease progression (identifying those who will progress to T1D from those who will not), and a signature of rate of progression. The third specific aim is to ask if there is a PBC gene expression signature that might predict responder vs. non-responder phenotypes for intervention with CTLA4-Ig in recent onset hyperglycemic patients using TN09 samples. The studies described in this application require PBC RNA samples from TrialNet. We have already received >300 samples from the TrialNet repository and have received provisional approval to receive additional samples (letter attached).

概括在这笔资助中，我们建议对外周血细胞进行基因表达分析 T1D 患者自身抗体阴性一级亲属 (AA- FDR) 和 AA+ 的 PBC 已进展（进展者）或未进展为高血糖（非进展者）的 FDR 进展者），与健康的非 T1D 相关对照相比。我们还将进行基因参加 TrialNet Abatacept (CTLA4-Ig) 的患者 PBC 表达分析新发病研究（TN-09）。拟议的研究将证实并扩展我们的工作鉴定疾病易感性和疾病进展的全血生物标志物 T1D，并启动我们对治疗反应的生物标志物的研究。在 JDRF 资助下产生的初步数据表明，PBC 基因 T1D 和 T1D 相关个体的表达谱彼此更相似，而不是健康正常的非糖尿病相关对照；也就是说，存在前驱基因表达可以识别未显示出 AA-FDR 的 T1D 患者 PBC 中疾病风险的特征疾病的临床症状。根据这些初步数据，我们假设 T1D 家族患者都具有环境驱动的、表观遗传控制的基因表达特征外周血中可见的风险。我们确定了 AA-FDR 的一个子集 PBC 中干扰素诱导的基因表达水平升高。这些人还表达的基因表达特征与 AA+ FDR 更相似，后者进展为与未进展的 AA+ FDR 或其他 AA- FDR 以及对照相比，高血糖，表明全血基因表达生物标志物可用于识别个体谁将在血清转化之前发展为高血糖。在血清转化的患者中 (AA+)，我们发现基因表达在疾病早期阶段变化最大(>3 进展者与非进展者相比，在高血糖发生前的几年内。这表明我们或许能够识别出不仅能够区分 AA+ 进展者的生物标志物 AA+ 非进展者，还可预测疾病进展率。最后，学习研究表明，近期发病的高血糖患者的 PBC 基因表达特征有所不同与那些没有反应的人相比，对抗 CD3 治疗有反应的人（AbATE 试验）。我们假设我们也可能会看到对以下药物有反应的患者的基因表达存在差异开始治疗 3 个月后，与没有反应的患者相比，CTA4-Ig（阿巴西普）疗法（TN-09）。如果能够及早识别出无反应者，就可以为其他人留出时间在β细胞质量/功能完全丧失之前测试疗法。提出了三个具体目标。第一个具体目标是验证前驱症状糖尿病相关 AA-个体中观察到的基因表达模式。第二个具体目标是鉴定 T1D 疾病进展的 PBC 基因表达特征（鉴定那些谁将从那些不会进展为 T1D 的人中），以及进展速度的签名。这第三个具体目标是询问是否存在可以预测的 PBC 基因表达特征近期发病时 CTLA4-Ig 干预的反应者与非反应者表型高血糖患者使用 TN09 样本。本申请中描述的研究需要来自 TrialNet 的 PBC RNA 样本。我们已经从 TrialNet 收到了超过 300 个样本存储库并已获得接收额外样品的临时批准（信件随附的）。