Multiomic level analyses in atypical diabetes patient derived iPSC and pancreatic cells- key to function

Diabetes affects more than 400 million of people worldwide, according to the International Diabetes Federation, and in Poland alone displays an upward trend with 2.8 million.

Maciej Maurycy Łałowski

Currently there is no cure for severe diabetes in humans. Diabetes is characterized by the abnormal glucose turnover where its levels in blood serum are controlled by the coordinated action of pancreatic hormones. One of such hormones, called insulin, which is produced by the pancreatic islet β-cells is accountable for glucose uptake into the other cells in the organism. Thus, an inadequate number of β-cells in the body or their malfunction leads to a condition with higher levels of glucose, called hyperglycemia, which in turn leads to diabetes.

The prevalence of diabetes in the Western world is increasing due to the diet and a lifestyle, and the age of newly diagnosed affected individuals is systematically lower. The gathered evidence points to β-cells as the main culprit in the development of diabetes. Even though diabetes is considered as a metabolic disease, majority of research so far related to the global changes in the genome (DNA level), transcriptome (RNA level), a couple of studies have focused on proteins while only a few look into the changes of various metabolites (e.g. lipids, sugars or aminoacids). So far, the comprehensive quantitative analysis at various levels of cellular organization has not yet been done. Thus, to fill these gaps-of-knowledge we are proposing a comprehensive study of focusing on changes at the RNA level (global transcriptome analysis), proteome (global and mitochondrial proteome analyses), and metabolome (global and specific studies of metabolites), to pinpoint the differential changes associated with human β-cell development, and diabetes. To achieve this goal, we decided to employ the human pancreatic cells differentiation model employing human induced pluripotent stem cells, which are capable of recapping the human β-cell development in vitro, bringing the repertoire of key developmental events in the cell dish (in vitro situation). To simultaneously learn about human diabetes, we chose a specific form of diabetes, called a ketosis prone (KPD form), and we will exploit the human induced pluripotent stem cells derived from a patient with this form of a disease. To realize the goals of the project we have established two specific aims. In aim 1, we expect that by performing the comprehensive analyses at different levels of cellular organization we will uncover the specific signaling cues behind the development of b-cells. In the second aim, we propose to utlize the same repertoire of techniques in combination with various functional analyses of b-cells, to define the molecular pathogenesis of a diabetes syndrome and pinpoint new potential routes for future clinical procedures and drug discovery.

This project will be performed at the Host institution (Adam Mickiewicz University- Poznan, Poland), in a laboratory headed by the Prof. Malgorzata Borowiak, who has an extensive expertise in diabetes studies, employing innovative methods of human pluripotent stem cell differentiation towards pancreatic β-cells. The PI of the proposal, Assoc. Professor Maciej Lalowski specializes in modern mass spectrometry and an expert in multiple data integration. By combining the expertise of both the PI and the Host laboratory, we expect to reveal in detail the cellular mechanism underlying diabetes.

Project details

Project title: Multiomic level analyses in atypical diabetes patient derived iPSC and pancreatic cells- key to function
Principal Investigator: dr hab. Maciej Maurycy Łałowski
Host institution: Adam Mickiewicz University in Poznań
Project duration: 01.11.2022 – 31.10.2024
Project’s website: www.maclal1-polonezbis.web.amu.edu.pl

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