Role of trefoil factor family proteins in beta cell function.

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.