Grant Number: 1R01AI081811 - 01 PI Name: FARR , ANDREW G Productive differentiation of thymic epithelium is critical for thymopoiesis and the establishment of self-tolerance. However, the differentiation program that forms the thymic environment is not well understood. Studies proposed here are intended to test a number of hypotheses that collectively constitute a model of TE differentiation that runs counter to the prevailing view, which has considered TE to be a fairly static population; one that is specified early during organogenesis to a thymic fate and that requires the Foxn1 transcription factor to complete the post-specification program of TE differentiation. We are proposing that uncommitted TE progenitor cells persist in the postnatal thymus and that their progeny are continually being specified to a thymic fate through the action of Foxn1. According to this model, transient expression of Foxn1 defines a critical determining step in TE differentiation. We also propose that the maintenance of progenitor and/or immature TE in the postnatal thymus is dependent on fibroblast growth factor signaling. Experiments proposed here will evaluate the impact of alterations of this signaling pathway on TE differentiation and determine the developmental potential and molecular profiles of TE that we propose to represent discrete early stages of TE differentiation. Interference with this signaling pathway may contribute to the phenomenon of age-related involution, while stimulation of this pathway may lead to the identification of different populations of TE progenitor cells with unique developmental potentials and may have important clinical value.
Thymic epithelial stem cells persist in the adult thymus, but their differentiation potential seems to decline with advancing age, leading to thymic involution. Understanding the program of thymic epithelial differentiation and the regulation of the program is necessary to reverse thymic involution and the loss of immune function that occurs in the elderly.
