Novel sources of insulin-secreting cells
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Partners
Fondazione Umberto Di Mario has been constituted in 2000 on initiative of a group of exponents of the Italian scientific world.
Disease
Type 1 diabetes
Type 1 diabetes (T1D, also known as juvenile diabetes) can occur at any age, but most commonly is diagnosed from infancy to the late 30s. In this type of diabetes, a person's pancreas produces little or no insulin. T1D is an autoimmune disease in which insulin-producing islet b-cells are selectively destroyed by autoaggressive T cells as a result of a complex interplay between genetic, immunologic and environmental factors.
The lack of insulin and the consequent hyperglycemia leads to a plethora of severe complications such as nephropathy, retinopathy, neuropathy and cardiovascular diseases. Therefore, it has become urgent to improve T1D pathogenesis comprehension, as well as T1D prevention and therapy, considering that insulin treatment can only delay the onset of diabetes-associated complications. T1D is a polygenic disorder where loci within the HLA (Human Leukocyte Antigen) account for most of genetic susceptibility. Non-genetic factors, most likely environmental, are also involved in the pathogenesis of the disease resulting in a T cell mediated autoimmune attack against pancreatic beta cells.
Although during the last decades our understanding of the natural history of T1D has significantly improved, the pathogenesis of this disease remains elusive and successful strategies for primary intervention are still to come. Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which causes an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. These systemic or organ-specific conditions are the results of multi-factorial processes involving dysregulation of the innate and adaptive immune systems that lead the body to attack its own tissues.
Incidence of the disease
T1D incidence is doubling approximately every 20-25 years, and an increasing number of people worldwide suffers from T1D, chronically lacking of insulin. Rates vary widely in different countries from a low of 0.1 cases/100,000 people/year in China and Venezuela to a high of 37 cases/100,000 people/year in Finland and Sardinia.
Overall, it has been reported that 437,500 children were affected by T1D worldwide in 2007 and about 70,000 children aged under 14 years are developing T1D per year, with a reported annual global increase of about 3%, particularly in younger children.
Project
Rational basis of the project
MicroRNAs (miRNAs) are a recently identified class of small cellular RNAs, whose function is to pair the miRNAs of protein-coding genes with subsequent transcriptional and post-transcriptional regulation of gene expression. miRNAs have emerged as important regulatory factors involved in developmental processes, such as neural progenitor cell growth and differentiation, and their altered expression has been observed in a large number of malignancies.
In addition, increasing evidence has shown that miRNAs are involved in the development of endocrine pancreas as well as in the regulation of insulin secretion and insulin signaling. Furthermore, a number of studies have revealed an altered miRNA profiling in lymphocytes of patients with autoimmune diseases like multiple sclerosis or rheumatoid arthritis, suggesting that an altered miRNA expression may contribute to autoreactivity.
Goal of the project
Beta-cell replacement therapy represents a potential cure for type 1 diabetes mellitus, and a detailed understanding of the molecular process involved in the regulation of beta cell mass, survival, and regeneration will provide key basic principles for new therapeutic technologies.
The hypothesis supporting our project is that modulation of miRNAs expression can be used as a tool for a successful in vitro expansion and differentiation of insulin-secreting cells from candidate precursors. To this end, we plan to analyze the miRNA expression profiles during in vitro expansion and re-differentiation of human islet-derived progenitor cells and to identify the impact of miRNAs modulation (by silencing or by overexpression) on the proliferation and differentiation processes of human islet-derived progenitor cells. The final result would be a reversal of the insulin secretion deficit and the possibility to avoid exogenous insulin administration in type 1 diabetes patients.
Rare Partners will work with the project’s partner institution (Fondazione Umberto Di Mario) with the aim to complete the proof of principle validation of the product both in vitro and in experimental animal models.