Molecular determinants of thyroid cell functional plasticity

点击翻译按钮获取中文摘要

The thyroid gland is essential for normal development and function in many species. The key functional entity in the thyroid gland is the angio-follicular unit (AFU) which comprises specialized thyroid epithelial cells and a surrounding network of blood vessels lines by endothelial cells. The intricate specialization (differentiation) of these cell types in AFU is essential for thyroid hormone production. Currently, information is lacking on the molecular drivers for the close structural association between thyroid cells and endothelial cells. We don’t know whether thyroid stem cells or differentiated thyroid cells communicate to endothelial cells. The role for pericytes, supporting cells for blood vessels, in AFU formation is unknown. My research program investigates the cellular and molecular drivers for AFU diferentiation and explores how environmental compounds interfere with critical processes regulating thyroid AFU maturation. I will focus on two mechanisms which influence aspects of cell differentiation in AFU: (1) recruitment and differentiation of blood vessel endothelial cells as a key requirement in establishing this intricate structure-function unit, and (2) the influence of structural changes at chromosomal telomeres in the cell nucleus on the dynamic differentiation in AFU. Nuclear telomeres are the protective ends of mammalian chromosomes and their organization in the nucleus was shown to change with cell differentiation. Although telomeres are protected by proteins they are explicitly sensitive to oxidative stress. Many environmental contaminants can induce oxidative stress in cells. My research investigates whether changes to the telomere organization in the nucleus caused by environmental inducers of oxidative stress will impair cell differentiation in AFU. Methodology: In my lab, we have established techniques for the isolation and culture of thyroid cells, the manipulation of cell differentiation and the two- and three-dimensional co-culture of thyroid epithelial and endothelial cells. I will use a unique three-dimensional (3D) cell culture model involving three key cell types for AFU formation: thyroid cells, endothelial cells and pericytes. I will identify proteins produced by thyroid (stem) cells which stimulate endothelial cell growth and blood vessel formation in AFU and will investigate whether environmental factors interfere with this process. I will utilize selected environmental compounds to induce oxidative stress at telomeres with resulting changes to the telomere organization. I will explore the impact of these structural telomere changes on the ability of cells to differentiate into AFU. This work utilizes superresolution microscopy techniques to visualize structural changes at telomeres in the nucleus. I will use 3D fluorescence imaging and electron microscopy techniques to detect cell type and cell differentiation markers in AFU. I will use utilize functional tests to monitor functional maturation of AFU. Novelty/ expected significance: This research will discover proteins which drive endothelial recruitment in thyroid AFU functional differentiation and will establish, for the first time, a role for pericytes in this fundamental biological process. This work will, for the first time, explore the role for nuclear telomeres as molecular targets for environmental compounds and link the resulting structural telomere alterations to impaired cell differentiation in the thyroid. Our findings will initiate new discoveries linking environmental signaling with nuclear structural changes impacting on differentiation processes.