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

• 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
• 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

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 在这笔赠款中，我们建议对外周血细胞进行基因表达分析 T1D患者（AA-FDR）和AA+的自动抗体负面亲戚（PBC）（PBC） 进步（进度者）或不发展高血糖的FDR（非 - 与健康的非T1D相关对照相比，进度者）。我们还将执行基因 对参加试验网abatacept（CTLA4-IG）新的患者的PBC的表达分析 发作研究（TN-09）。拟议的研究将确认并扩展我们在 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。 JDRF资助下产生的初步数据表明PBC基因 T1D和T1D相关个体的表达曲线比彼此更相似 健康的正常非糖尿病相关对照；也就是说，有一个前驱基因表达 可以鉴定出T1D患者AA-FDR的PBC中可以识别疾病风险的签名 疾病的临床体征。基于这些初步数据，我们假设T1D家族 患者都有环境驱动的，表观遗传控制的基因表达特征 外周血中可以看到的风险。我们确定了一个aa-fdr的子集 干扰素诱导的基因表达水平升高。这些人也是如此 表达了一个基因表达签名，该签名与进展到的AA+ FDR更相似 高血糖比没有进步或其他AA-fdr的AA+ FDR和对照 建议全血基因表达生物标志物可用于识别个体 在血清转化之前，谁将发展为高血糖。在血清转化的患者中 （aa+），我们发现在疾病的早期阶段，基因表达发生了最大的变化（> 3 与非传播者相比，在高血糖发作之前的几年。这 表明我们可能能够识别不仅区分AA+经验者的生物标志物 来自AA+非培训器，但也可以预测疾病进展的速度。最后，研究 已经表明，最近发作高血糖患者的PBC基因表达特征有所不同 与没有反应的患者相比，这对抗CD3疗法做出了反应（缓解试验）。我们 假设我们还可能看到对反应的患者的基因表达差异 与那些没有回应的人相比 治疗（TN-09）。如果可以提早确定非反应者，这将使其他时间有时间 在发生总β细胞质量/功能的总损失之前要测试的疗法。 提出了三个具体目标。第一个具体目的是验证前驱 与糖尿病相关的基因表达模式。第二个具体目标是 识别T1D疾病进展的PBC基因表达特征 谁会从那些不愿意的人和进步率的签名中发展为T1D。这 第三个具体目的是询问是否存在PBC基因表达签名 响应者与无反应表型用于干预CTLA4-Ig最近发作 使用TN09样品的高血糖患者。本应用中描述的研究需要 来自试验网的PBC RNA样品。我们已经从试用网中收到了> 300个样本 存储库并已获得临时批准以接收其他样本（信函 随附的）。