News & Research

    University of Michigan, Ann Arbor, Michigan

Molecular basis and control of endocrine determination by the Presenilins

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Islet Biology\Beta Cell Growth and Differentiation

Type of Grant: Junior Faculty

Project Start Date: July 1, 2011

Project End Date: June 30, 2014

Research Description

Objective: Our goal is to define the molecular steps in early pancreatic development that involve commitment of precursor cells to choose between acinar or endocrine fate and to manipulate that system genetically and pharmacologically to enhance the pool of beta-cells obtained from embryonic or adult tissues.

Background: The pancreatic precursor cells differentiate into acinar cells secreting digestive enzymes, and endocrine cells secreting insulin. Early in development, the Notch signaling pathway is the major player directing the fate of the pancreatic precursors.. Our recent studies, utilizing sophisticated mouse genetic models (Presenilin mice), in which we can alter Notch signaling in specific pancreatic cells at chosen times during development, have allowed us to demonstrate that this pathway still controls the fate of endocrine progenitors at later stages.

Anticipated outcome: Using a combination of genetic models, Specific Aim 1 will allow us to indentify the precise targets of the Presenilins that control endocrine fate and proliferation. Specific Aim 2 will employ an additional model to analyze the molecular mechanisms allowing the switch between endocrine and acinar fate in the Presenilin-deficient progenitors. We will manipulate the enzymatic activity of Presenilin to alter the endocrine/acinar balance in culture during pancreatic development (Aim 3) to test the hypothesis that this will increase the number of endocrine cells that can be derived from progenitors.

Relevance: We believe that the results of these experiments will serve to accelerate efforts towards the development of cell-based therapies for diabetes.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

This project is relevant to both Type 1 and Type 2 diabetes. In both forms of diabetes, the progression of the disease results from an insufficiency of the β-cells to respond to the demand in Insulin (either following a loss of β-cells, or because insulin resistance increased the demand beyond what the pancreas can produce). When the destruction of the β-cells is too advanced, cell therapy looks like the most promising treatment option, but donors are rare and patients are in desperate need of large number of islets.

The goal of this proposal is to identify (and manipulate) the early steps during development allowing pancreatic progenitors to progress to fully mature endocrine cells. This knowledge could then be used to attempt to manipulate, genetically or pharmacologically, cells in culture or in vivo to enhance the generation of Insulin-secreting cells from different sources of progenitors.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

We believe that these experiments will serve to accelerate efforts towards the development of cell-based therapies for the treatment of diabetes.

Preliminary experiments allowed us to identify a pathway that is key in the early control of the differentiation of progenitors into mature β-cells. The experiments depicted in this proposal are targeted at identifying the precise role of the different members of this pathway. We anticipate that their manipulation, in culture, or in mouse models, should demonstrate how this could be used to increase the number of endocrine cells that can be derived from various progenitors.

We believe that these experiments will constitute an important step allowing us to derive larger numbers of endocrine cells from progenitors, a prerequisite for effective cell-based therapy. If our experiments are successful, they could allow a significant increase in the mass of cells that can be generated for transplantation.

The number of people who suffer from Diabetes has risen to higher and higher numbers in the past few decades. We all have relatives and loved ones who had to suffer from diabetes itself and the tremendously invalidating side effects that result from the disease.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

I have been working on pancreatic development and diabetes research for my entire scientific career: From my undergraduate studies, to my PhD, my postdoctoral fellowship and now in my current position.

This award will allow me to pursue a research project I have been carrying with me for many years and that I truly believe to be of significance to help diabetes patients.

Diabetes can result from multiple causes (genetic, environmental, etc.). This is one of the aspects that make it such a complex challenge for the treatment of the patients, and diabetes research as a whole.

In what direction do you see the future of diabetes research going?

Two main aspects seem to emerge from the current research efforts: research on the prevention of diabetes and the 'protection' of pre-existing cells, in order to help patients in the earliest stages of the progression of the disease, and the research on treatments (such as cell-based therapy) for patients in a more advanced stage.

Both fields are equally important in my eyes, but target a different population of patients.

As far as cell-based therapy goes, I see the future of the research going in the generation of β-cells from progenitors or from transdifferentiation from other, more abundant and readily available cell types, such as acinar cells.

Significant progress has recently been made to reprogram cells to become endocrine cells. If functional cells can be generated in sufficient numbers, this approach would allow autografts without the need for immunosuppressive therapies.