Non-receptor tyrosine kinases in beta-cells

胰腺细胞是胰腺中的特化细胞。它们的生物学作用是独特的：它们分泌胰岛素以维持血糖在一个相对狭窄的生理范围内。因此，β细胞受到营养和环境因素的调节，这些因素以寡源方式起作用。然而，它们的调控（以及潜在的分子机制）尚未完全被理解，这是一个令人着迷的生物学难题。我的总体研究计划是研究控制β细胞诞生、生存和死亡的分子机制。使用药理学和生化方法，我们之前发表了Src家族成员可以调节β细胞的“生与死”。然而，我们没有准确地确定参与这一过程的Src成员。因此，本研究的目的是研究β细胞中最丰富的Src成员的生物学作用。更准确地说（基于我们丰富的初步数据），我们建议对Src和Lyn缺失/激活对β细胞质量、胰岛形态和葡萄糖稳态的影响进行彻底的研究。三个相互关联的特定目标将同时进行：Aim 1将研究Src成员在体内β细胞的生命和死亡（增殖和存活）中的作用；Aim 2将研究Src成员在体外β细胞的生命和死亡中的作用；Aim 3将研究Lyn在β细胞中的靶标。该研究计划将确定控制β细胞质量调节的新型信号效应物，从而回答关键的生物学问题。这个研究项目完全符合我的实验室的重点，并建立在我在分子信号方面的专业知识。它涵盖了几个研究领域（生物化学、细胞和分子生物学、基因组学、代谢组学），因此是培养高素质人才的理想平台。

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.