Role of trefoil factor family proteins in beta cell function.

三叶因子家族蛋白在β细胞功能中的作用。

基本信息

批准号：
10566731
负责人：
Patrick T. Fueger
金额：
$ 56.5万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-20 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566731
关键词：
1 year old Address Adult Affect American Bacteria Beta Cell Biological Models Birth Brain Cell Communication Cell physiology Cells Child Chronic Disease Cities Closure by clamp Compensation Complex Cysteine Data Defect Development Diabetes Mellitus Diabetes prevention Disease Disulfides Ductal Epithelial Cell Eating Elderly Embryo Environment Epithelial Cells Epithelium Exhibits Exocrine pancreas Extracellular Matrix Proteins Family Functional disorder Gel Glucose Intolerance Goals Human Hyperglycemia Impairment In Vitro Incidence Infiltration Injury Institution Insulin Intervention Islet Cell Islets of Langerhans Knockout Mice Knowledge Lung Lymphoid Tissue Metabolic Molecular Mucins Mucous body substance Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Palmitic Acids Pancreas Parasites Pathogenesis Pattern Peptide Hydrolases Peptides Peripheral Personal Satisfaction Play Population Prediabetes syndrome Prevention Protein Family Protein Secretion Proteins Proteomics Research Resistance Rodent Role Stimulus Stress TFF1 gene Teenagers Testing Thick Thyroid Gland Tissues Translations United States Virus Work aged blood glucose regulation cell type diabetes pathogenesis diabetogenic endocrine pancreas development epithelial repair gastrointestinal human tissue in vitro Model in vivo innovation insulin secretion insulin sensitivity islet knock-down knockout gene mouse model new therapeutic target novel novel therapeutics overexpression prevent public health relevance receptor response tool trefoil factor western diet young adult

项目摘要

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.

修改后的项目摘要/摘要部分在美国，近 10% 的人口（超过 3000 万）患有 2 型糖尿病 (T2D)，而且这一数字不仅在老年人中不断增长，而且在儿童、青少年和年轻人中也在增长。 T2D 发病率令人震惊且持续增加，尤其是在美国年轻人中，迫切需要新的治疗方法和干预措施。导致 T2D 的根本原因之一是 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，但人们对微环境（例如外分泌胰腺的分泌因子）如何影响发病机制知之甚少。三叶因子家族肽（TFF1、TFF2 和 TFF3）是独特的分泌蛋白，因为它们含有六个半胱氨酸残基，形成三个分子内二硫键，这使得它们更加稳定并且能够抵抗蛋白酶和其他恶劣条件。三叶因子已被证明在维持肠道和肺上皮的完整性以及损伤后修复上皮细胞方面发挥着重要作用。三叶因子在胰腺中表达，但其作用尚不清楚。我们的初步数据表明，Tff2 由外分泌胰腺表达，胰腺中该基因的敲除会导致成年小鼠的 β 细胞功能障碍。然而，Tff2 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 Tff2 可以防止糖尿病应激的破坏性影响。我们将使用 Tff2 的胰腺特异性敲除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 Tff2 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。在目标2中，我们将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，并利用体外模型系统研究外分泌细胞和胰岛细胞之间通过TFF2的串扰。我们将使用创新工具来测试关于希望之城以翻译为中心的制度环境中三叶因子作用的新假设。这项工作将通过解决糖尿病预防/治疗的一个有前途的候选分泌因子来对糖尿病研究产生积极影响。