Nkx6 gene function in pancreas development

描述(申请人提供)：糖尿病是由胰腺中产生胰岛素的β细胞丢失或功能障碍引起的。尽管胰岛素注射方案精细化，但糖尿病患者仍存在长期并发症，如失明和肾衰竭。糖尿病的最终治愈可以通过产生替代的胰岛素产生细胞来实现。为了发展这些替代细胞，我们需要确定启动β细胞形成和胰岛素产生的分子途径。利用基因工程小鼠模型，这项建议研究了NKX6类转录因子在β细胞分化和功能中的作用。具体的假设是不同的NKX6转录因子在胰腺细胞分化过程中部分互补彼此的功能。这一假说是基于观察到Nkx6.1突变小鼠的β细胞数量减少，而Nkx6.1/Nkx6.2双突变小鼠显示产生胰岛素的β细胞和产生胰高血糖素的α细胞都减少了。有人提议利用NKX6基因的复合小鼠突变体来剖析NKX6因子在胰腺内分泌发育中的作用。目的1是通过尝试恢复具有不同转基因的Nkx6.1突变小鼠的β细胞发育，确定NKX6因子在β细胞分化途径中的作用。目的2在小鼠中检测在缺乏NKX6活性的情况下，胰腺前体细胞是否会回复到另一种细胞命运。目的3研究NKX6因子在成人胰岛β细胞功能中的作用。通过在β细胞中选择性地灭活NKX6基因，将研究NKX6因子是否控制β细胞功能的各个方面，如胰岛素合成或胰岛素分泌。

DESCRIPTION (provided by applicant): Diabetes mellitus results from loss or dysfunction of the insulin-producing beta-cells in the pancreas. Despite refined insulin injection regimens, diabetic patients suffer from long-term complications, such as blindness and kidney failure. An ultimate cure for diabetes could be achieved through the generation of replacement insulin-producing cells. To develop these replacement cells, we need to identify the molecular pathways that initiate beta-cell formation and insulin-production. Using genetically engineered mouse models, this proposal examines the role of NKX6 class transcription factors in beta-cell differentiation and function. The specific hypothesis is that different NKX6 transcription factors partially compensate for each other's function in pancreatic cell differentiation. This hypothesis is based on the observation that beta-cell numbers are diminished in Nkx6.1 mutant mice, while Nkx6.1/Nkx6.2 double mutant mice show a reduction in both insulin producing beta- and glucagon-producing alpha-cells. Experiments are proposed to dissect the role of NKX6 factors in pancreatic endocrine development using compound mouse mutants for Nkx6 genes. Aim 1 is to define the role of NKX6 factors in the beta-cell differentiation pathway by attempting to restore beta-cell development in Nkx6.1 mutant mice with different transgenes. Aim 2 examines in mice if pancreatic progenitors are reverted into alternate cellular fates in the absence of NKX6 activity. Aim 3 focuses on the role of NKX6 factors in adult beta-cell function. Using selective inactivation of Nkx6 genes in beta-cells, it will be studied if NKX6 factors control aspects of beta-cell function, such as insulin synthesis or insulin secretion.