Project Abstracts - CBDS

Yuval Dor, PhD, co-Investigator, Hebrew University of Jerusalem
Ruth Shemer, PhD, co-Investigator, Hebrew University of Jerusalem
Jorge Ferrer, MD, PhD, co-Investigator, Imperial College of London

Start Date: September 23, 2014
End Date:  August 31, 2018

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Abstract

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).

Publications

• The DNA methylome of human vascular endothelium and its use in liquid biopsies
• A DNA methylation atlas of normal human cell types
• B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies
• Remote immune processes revealed by immune-derived circulating cell-free DNA
• Multiplexing DNA methylation markers to detect circulating cell-free DNA derived from human pancreatic beta-cells
• Insulin-Like Growth Factor Dysregulation Both Preceding and Following Type 1 Diabetes Diagnosis
• Digital Droplet PCR for Monitoring Tissue-Specific Cell Death Using DNA Methylation Patterns of Circulating Cell-Free DNA
• Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease
• β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes
• Monitoring liver damage using hepatocyte-specific methylation markers in cell-free circulating DNA
• Postnatal Exocrine Pancreas Growth by Cellular Hypertrophy Correlates with a Shorter Lifespan in Mammals
• Non-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA
• Understanding Pre-Type 1 Diabetes: The Key to Prevention
• Beta Cell Death by Cell-Free DNA and Outcome after Clinical Islet Transplantation
• Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers
• Type 1 diabetes mellitus
• Metabolic Stress and Compromised Identity of Pancreatic Beta Cells
• Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes
• PAX6 maintains β cell identity by repressing genes of alternative islet cell types
• The Genetic Program of Pancreatic β-Cell Replication In Vivo
• Identification of tissue-specific cell death using methylation patterns of circulating DNA