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。

• 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
• 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

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），这一数字不仅在老年人，而且在儿童，青少年和年轻人中也在增长。 T2D发病率的令人震惊和持续的增加，尤其是在年轻的美国人中，迫切需要新的治疗和干预措施。导致T2D的潜在条件之一是β细胞功能障碍。尽管发现导致其功能障碍的β细胞的分子变化一直是该领域的集中精力，但对微环境（例如来自外分泌胰腺的分泌因子）如何也可能有助于发病机理的微环境如何了解。三叶因子家族肽（TFF1，TFF2和TFF3）是独特的分泌蛋白质，因为它们含有六个半胱氨酸残基，它们形成了三个分子内二硫键桥，这使它们对蛋白酶和其他恶劣条件具有更稳定和耐药性。三叶草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起着至关重要的作用。三叶剂因子在胰腺中表达，但其作用尚未得到很好的理解。我们有初步数据表明，TFF2是由外分泌胰腺表达的，并且该基因在胰腺中的敲除导致成年小鼠的β细胞功能障碍。但是，TFF2在β细胞上施加的分子和细胞机制尚不清楚。我们的中心假设是TFF2可以防止糖尿病胁迫的破坏作用。我们将使用胰腺特异性的TFF2和原代人体组织/细胞的小鼠模型进行研究。在AIM 1中，我们将研究鼠胰腺中缺乏TFF2如何影响老年小鼠和糖尿病生成状况下的β细胞功能障碍。在AIM 2中，我们将通过使用体外模型系统通过TFF2来阐明人类胰腺组织中Trefoil因子家族蛋白及其受体的分布模式，并通过TFF2研究外分泌和胰岛细胞之间的串扰。我们将使用创新的工具来测试有关希望之城以翻译为重点的机构环境中有关三叶草因素的行为的新假设。这项工作将通过解决预防糖尿病/治疗的有希望的候选分泌因素来积极影响糖尿病研究。