Non-receptor tyrosine kinases in beta-cells

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Pancreatic beta-cells are specialized cells residing in the pancreas. Their biological role is unique: they secrete insulin in order to maintain blood glucose in a relatively narrow physiological range. As such, beta-cells are regulated by nutritional and environmental cues that act in an oligogenic fashion. However, their regulation (and the underlying molecular mechanisms) is not completely understood and represents a fascinating biological puzzle. My overall research program investigates the molecular mechanisms governing beta-cell birth, life and death. Using pharmacological and biochemical approaches, we previously published that members of the Src family could regulate beta-cell "life and death". However, we did not precisely identify the Src members that were involved in this process. Thus, the goal of this proposal is to investigate the biological roles of the most abundant Src members in beta-cells. More precisely (and based on our abundant preliminary data), we propose to conduct a thorough investigation of the consequences of Src and Lyn deletion/activation on beta-cell mass, pancreatic islet morphology, and glucose homeostasis. Three inter-related specific aims will be concurrently pursued: Aim 1 will investigate the role of Src members in beta-cell life and death (proliferation and survival) in vivo Aim 2 will investigate the role of Src members in beta-cell life and death in vitro Aim 3 will investigate the targets of Lyn in beta-cells This research program will identify novel signaling effectors that govern the regulation of beta-cell mass, thereby answering key biological questions. This research program perfectly aligns with the focus of my laboratory and builds on my expertise in molecular signaling. It encompasses several fields of research (biochemistry, cellular and molecular biology, genomics, metabolomics) and thus constitutes an ideal platform for the training of highly qualified personnel.