Role of trefoil factor family proteins in beta cell function.

修改项目摘要/摘要部分 在美国，近10%的人口（超过3000万）患有2型糖尿病（T2 D），这一数字不仅在老年人中而且在儿童，青少年和年轻人中也在增长。T2 D发病率的惊人和持续增加，特别是在年轻的美国人中，迫切需要新的治疗和干预措施。导致T2 D的潜在条件之一是β细胞功能障碍。虽然发现β细胞中导致其功能障碍的分子变化一直是该领域的重点工作，但对微环境（如外分泌胰腺分泌因子）如何也可能导致发病机制知之甚少。三叶因子家族肽（TFF 1、TFF 2和TFF 3）是独特的分泌蛋白，因为它们含有形成三个分子内二硫键的六个半胱氨酸残基，这使得它们更稳定并且对蛋白酶和其他苛刻条件具有抗性。三叶因子已被证明在维持肠和肺上皮的完整性以及在损伤后修复上皮细胞中起重要作用。三叶因子在胰腺中表达，但其作用尚不清楚。我们有初步的数据显示，Tff 2是由胰腺外分泌表达的，在胰腺中敲除该基因会导致成年小鼠的β细胞功能障碍。然而，Tff 2对β细胞发挥作用的分子和细胞机制尚不清楚。我们的中心假设是Tff 2保护免受致糖尿病应激的破坏性影响。我们将使用我们的胰腺特异性敲除Tff 2小鼠模型和原代人类组织/细胞进行研究。在目标1中，我们将研究小鼠胰腺中Tff 2的缺乏如何影响老年小鼠和糖尿病条件下的β细胞功能障碍。目的2：阐明三叶因子家族蛋白及其受体在人胰腺组织中的分布模式，并通过体外模型系统研究外分泌与胰岛细胞之间通过TFF 2的串扰。我们将使用创新的工具来测试新的假设，在一个以预防为重点的制度环境中，在希望之城三叶因子的行动。这项工作将通过解决糖尿病预防/治疗的有前途的候选分泌因子对糖尿病研究产生积极影响。

Modified Project Summary/Abstract Section In the United States, nearly 10% of the population (more than 30 million) has type 2 diabetes (T2D) and this number is growing not only in older adults but also in children, teens, and young adults. The alarming and continued increase of T2D incidence, especially among young Americans, creates an urgent need for new therapeutics and interventions. One of the underlying conditions leading to T2D is the dysfunction of beta cells. While discovering the molecular changes in beta cells leading to their dysfunction has been a focused effort in the field, less is known about how the microenvironment, such as secreted factors from exocrine pancreas, may also contribute to pathogenesis. Trefoil factor family peptides (TFF1, TFF2, and TFF3) are unique secreted proteins in that they contain six cysteine residues that form three intramolecular disulfide bridges, which makes them more stable and resistant to proteases and other harsh conditions. Trefoil factors have been shown to play essential roles in maintaining the integrity of gut and lung epithelium, and in repairing epithelial cells after injury. Trefoil factors are expressed in the pancreas, but their roles are not well understood. We have preliminary data revealing that Tff2 is expressed by the exocrine pancreas and the knockout of this gene in the pancreas leads to beta cell dysfunction in adult mice. However, the molecular and cellular mechanisms by which Tff2 exerts on beta cells are unknown. Our central hypothesis is that Tff2 protects against the damaging effects of diabetogenic stress. We will use our pancreas-specific knockout mouse model of Tff2 and primary human tissues/cells for our studies. In Aim 1, we will examine how the lack of Tff2 in the murine pancreas affects beta cell dysfunction in aged mice and under diabetogenic conditions. In Aim 2, we will clarify the distribution patterns of trefoil factor family proteins and their receptors in human pancreatic tissues and study the crosstalk between exocrine and islet cells via TFF2 by using in vitro model systems. We will use innovative tools to test novel hypotheses on the actions about trefoil factors within a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by addressing a promising candidate secretory factor for diabetes prevention/treatment.