Principal Investigators:
Dr Masashi Narita , University of Cambridge
Dr Ittai Ben-Porath , The Hebrew University of Jerusalem
Overview
Ageing is characterized by reduced functionality and regenerative capacity of tissues. Among the most common features of ageing is the deterioration in the physiologic ability to process glucose, which often leads to type 2 diabetes. This process dramatically reduces quality of life, and is associated with increased risk of other diseases, including cancer and heart failure. Recent studies have discovered that cellular senescence, a state of persistent cellular stress and proliferative arrest, contributes greatly to tissue ageing. Thus, generally, cellular senescence is detrimental in tissue homeostasis. However, we recently discovered that during normal ageing, beta-cells in the pancreas undergo senescence. Beta-cells are responsible for secreting insulin when blood glucose levels are high, and their function is therefore critical in diabetes. Counter-intuitively, we found that insulin secretion by these cells is enhanced upon senescence.
In this project, Professor Narita and Professor Ben Porath will address the roles of beta-cell senescence in ageing and diabetes in depth. Their aim is to uncover whether beta-cell senescence contributes to, or, alternatively acts to counteract diabetes. In either case, they will explain the molecular mechanisms behind the functional effects of senescent beta-cells. Using a variety of human and mouse models, they will study how beta-cell senescence affects the disease. Regulation of gene activity, which is reprogrammed in senescence, underlies changes in function. The project will employ cutting edge genomic analyses to uncover how gene regulation is reorganized in senescent beta-cells.
Outcomes
This study will help in understanding the actions of senescent beta-cells, which could open the door towards targeting their pathways of actions as new modes of treatment. Although critical roles for senescence has been uncovered in the last two years, little is known about its contribution to diabetes, and particularly regarding the ability of the pancreas to secrete insulin to combat the disease. This study provides a new unexplored approach to dissecting and combating diabetes and decreased glucose tolerance with age.
The Partnership
The Ben-Porath group studies the roles of senescence in ageing and diabetes, and the Narita group works on gene regulatory mechanism in senescence. The Ben-Porath group provides all the relevant disease models and conduct functional analyses, and using those resources, the Narita group will conduct genomic and epigenomic experiments and systematic analysis of gene regulatory networks