Regulation of cell fate determination by hormone-active nutrients and phytochemicals

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Vitamin D plays important roles in the development of a variety of tissues including bones and teeth and more recently has been implicated as a central player in the differentiation and maintenance of a number of other tissues. Vitamin D deficiency is associated with abnormalities in blood cell development, neurological disorders, bowel disease, impaired immune function and increased incidence of obesity related diseases and certain forms of cancer. There are multiple receptors for active metabolites of vitamin D (1,25 dihydroxyvitamin D3 or calcitriol) including the classic nuclear and membrane vitamin D receptor (VDRnuc, VDRmem), but more recently, we and others have identified a novel membrane receptor that is genetically distinct from VDR. This protein is described as a Membrane Activated Rapid Response to Steroid (MARRS) receptor for vitamin D. It is known by a number of other names and has important roles in assisting with protein folding, response and survival of cells when stressed, and in the proper assembly of protein complexes that are important for immune cell function, particularly of B-cells. Hormone-active nutrients like vitamin D, rarely act on their own, more frequently interacting with other hormones, cytokines and other non-nutritive components of foods. The currently research program examines the mechanisms by which vitamin D acts in models of blood cell development and in maturation and function of breast epithelial tissues. In particular we are examining the role of MARRS in development of these tissues and how absence of its function interferes with normal decisions cells typically make about whether to proliferate, mature, change function or die. We use human cell culture models and molecular techniques to over-express or knock out MARRS, and examine how the cells respond to normal stimuli including 1,25 D3, fatty acids, cytokines and phytochemicals such as those found in red wine. We are also generating mice that have MARRS missing in certain blood cell lineages and in specific breast epithelial cells to examine the impact on development of these tissues in mice and the role for vitamin D in their development, maintenance of cell function and susceptibility to disease.