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Non-Invasive Diagnosis of Human Beta Cell Damage and Death

人类β细胞损伤和死亡的无创诊断

基本信息

批准号：
8813900
负责人：
DESMOND Arthur SCHATZ
金额：
$ 144.4万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-23 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813900
关键词：
Address Archives Basic Science Beta Cell Biological Assay Biological Markers Blood Blood Cells Blood Circulation Cell Death Cells Cellular biology Clinical Clinical assessments Collaborations DNA DNA Methylation Detection Diabetes Mellitus Diagnosis Diagnosis Clinical Trials Diagnostic Disease Early Diagnosis Failure Genomics Goals Human Human Biology Insulin-Dependent Diabetes Mellitus Measurement Methods Methylation MicroRNAs Monitor Non-Insulin-Dependent Diabetes Mellitus Nucleic Acids Onset of illness Patients Pattern Populations at Risk Process Research Sampling Sensitivity and Specificity Staging Stress Structure of beta Cell of islet Technology Tissues Transplant Recipients Variant abstracting base cell injury epigenomics healthy volunteer insight islet next generation sequencing novel nucleic acid detection pre-clinical public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): Non-invasive diagnosis of human beta cell damage and death Abstract Detection of beta cell damage or death in blood is an important challenge that could transform basic research, diagnosis and clinical trials in diabetes. We propose to establish novel, sensitive and quantitative methods for the detection of nucleic acids shed from damaged beta cells to blood, and to apply these methods in the context of human diabetes. In one approach, we will define a unique DNA methylation signature of beta cells and utilize next generation sequencing technology to detect and quantify signature DNA fragments released from dying beta cells to the circulation. In preliminary studies we found that this approach can robustly detect beta cell death in the blood of recently diagnosed type 1 diabetes patients and in patients transplanted with islets, while healthy donors show an extremely low background. In a second approach, we will quantify microRNAs released from damaged or dying beta cells to the circulation, focusing on combinations of beta cell-specific microRNAs. Here as well, preliminary studies on recently diagnosed type 1 diabetes patients suggest that beta cell damage (lethal or sub-lethal) can be reliably detected based on circulating microRNAs. We will then apply these complementary approaches to address fundamental questions in the biology of human diabetes, using both archived material and freshly isolated blood from patients and healthy volunteers. The proposal is close collaboration between three groups with complementary expertise: Schatz (clinical diabetes, biomarkers for early diagnosis), Ferrer (beta cell epigenomics and microRNA) and Dor (beta cell failure and DNA methylation).

摘要血液中β细胞损伤或死亡的检测是改变糖尿病基础研究、诊断和临床试验的重要挑战。我们建议建立一种新的、灵敏的、定量的方法来检测受损β细胞脱落到血液中的核酸，并将这些方法应用于人类糖尿病的研究。在一种方法中，我们将定义β细胞的独特DNA甲基化特征，并利用下一代测序技术检测和量化垂死的β细胞释放到循环中的特征DNA片段。在初步研究中，我们发现这种方法可以检测到新诊断的1型糖尿病患者和胰岛移植患者血液中的β细胞死亡，而健康供者的背景极低。在第二种方法中，我们将量化从受损或死亡的β细胞释放到循环中的microrna，重点关注β细胞特异性microrna的组合。同样，对新近诊断的1型糖尿病患者的初步研究表明，基于循环microrna可以可靠地检测到β细胞损伤（致命或亚致命）。然后，我们将应用这些互补的方法来解决人类糖尿病生物学中的基本问题，使用存档的材料和从患者和健康志愿者身上新分离的血液。该提案是三个具有互补专业知识的小组之间的密切合作：Schatz（临床糖尿病，早期诊断的生物标志物），Ferrer （β细胞表观基因组学和microRNA）和Dor （β细胞衰竭和DNA甲基化）。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes.

胰腺β细胞在啮齿动物和人糖尿病中表达胎儿胰岛激素胃癌。

DOI：
10.2337/db16-0641
发表时间：
2017-02
期刊：
Diabetes
影响因子：
7.7
作者：
Dahan T;Ziv O;Horwitz E;Zemmour H;Lavi J;Swisa A;Leibowitz G;Ashcroft FM;In't Veld P;Glaser B;Dor Y
通讯作者：
Dor Y

The DNA methylome of human vascular endothelium and its use in liquid biopsies.

人血管内皮 DNA 甲基化及其在液体活检中的应用。

DOI：
10.1016/j.medj.2023.03.006
发表时间：
2023
期刊：
Med (New York, N.Y.)
影响因子：
0
作者：
Peretz,Ayelet;Loyfer,Netanel;Piyanzin,Sheina;Ochana,BrachaLea;Neiman,Daniel;Magenheim,Judith;Klochendler,Agnes;Drawshy,Zeina;Fox-Fisher,Ilana;Fridlich,Ori;Moss,Joshua;Cohen,Daniel;Zemmour,Hai;Cann,Gordon;Bredno,Joerg;Venn,O
通讯作者：
Venn,O

Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA.

DOI：
10.1038/s41467-018-03961-y
发表时间：
2018-04-24
期刊：
Nature communications
影响因子：
16.6
作者：
Zemmour H;Planer D;Magenheim J;Moss J;Neiman D;Gilon D;Korach A;Glaser B;Shemer R;Landesberg G;Dor Y
通讯作者：
Dor Y

Remote immune processes revealed by immune-derived circulating cell-free DNA.

DOI：
10.7554/elife.70520
发表时间：
2021-11-29
期刊：
eLife
影响因子：
7.7
作者：
Fox-Fisher I;Piyanzin S;Ochana BL;Klochendler A;Magenheim J;Peretz A;Loyfer N;Moss J;Cohen D;Drori Y;Friedman N;Mandelboim M;Rothenberg ME;Caldwell JM;Rochman M;Jamshidi A;Cann G;Lavi D;Kaplan T;Glaser B;Shemer R;Dor Y
通讯作者：
Dor Y

Metabolic Stress and Compromised Identity of Pancreatic Beta Cells.