Colleen E. Hayes, Ph.D.

Biochemistry Building Rm 5507
420 Henry Mall
Madison WI 53706
608-263-6387
hayes@biochem.wisc.edu

Emphasis Group:
Biochemical & Molecular Nutrition

Principal Research Interest:
Molecular mechanisms that regulate immune responses

Research Summary:
We investigate molecular mechanisms that regulate lymphocyte development and function. One research area emphasizes how the hormones 1,25-dihydroxyvitamin D3 (calcitriol) and retinoic acid inhibit chronic autoimmune diseases like multiple sclerosis and arthritis through their actions on T lymphocytes. A second research area emphasizes how new B lymphocytes are directed to develop into long-lived memory B cell precursors.

Experimental autoimmune encepha-lomyelitis (EAE) is an autoimmune disease believed to be a model for the human disease, multiple sclerosis. EAE is induced by immunizing B10.PL mice with myelin basic protein, a constituent of the central nervous system. In a collaboration with Hector DeLuca, our lab discovered that administering calcitriol before inducing EAE completely prevented the progressive paralytic disease. More importantly, when calcitriol was provided after severe paralysis had occurred, the hormone reversed the disability symptoms. Withdrawal of calcitriol resulted in a resumption of progressive paralysis. Finally, a deficiency of vitamin D resulted in an increased susceptibility to EAE. Thus, calcitriol or its analogs are potentially important for treatment of multiple sclerosis. Retinoic acid has a similar effect on EAE.

Our current research goal is to elucidate how the hormones calcitriol and retinoic acid block progressive autoimmune disease. We hypothesize that these hormones are potent transcriptional inhibitors of several inflammatory cytokines, in particular interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12). We have shown that retinoic acid inhibits IFN-gamma transcription. Current experiments aim to map the retinoic acid responsive element in the IFN-gamma promoter and to characterize the retinoic acid-responsive proteins that bind to this element and transduce the retinoic acid signal into a process that limits IFN-gamma transcription. We plan similar studies for calcitriol. We will first identify the target cells for calcitriol action, and then investigate how calcitriol controls the cell's functions. Our preliminary data suggest that calcitriol stimulates synthesis of the anti-inflammatory cytokine transforming growth factor-beta.

Our second research area is B lymphocyte development. Our lab discovered a B cell intrinsic locus, Bcmd (B cell maturation defect), that causes most B lymphocytes to die prematurely before they become memory B cell precursors. Consequently, Bcmd mice have a profound peripheral B cell deficiency and they display no immunological memory. We are approaching the problem of identifying the Bcmd gene product and its function using biochemical and genetic methods. We are mapping Bcmd to facilitate positional gene cloning strategies. We are also studying growth factor receptor signal transduction and the synthesis of proteins like BCL-2 that block apoptosis in Bcmd B cells with the goal of learning where the mutant Bcmd gene product functions.

Representative Publications:

Nashold, F.E., D.J. Miller, and C.E. Hayes. 1,25-Dihydroxyvitamin D3 decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis. J. Neuroimmunology 103:171-179 (2000).

Nashold, F.E., Hoag K.A., Goverman, J., and Hayes C.E. Rag-1- dependent cells are necessary for 1,25-Dihydroxyvitamin D3 prevention of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 119:16-29 (2001).

Spach, K.M., L.B. Pedersen, F.E. Nashold, T. Kayo, B. Yandell, T.A. Prolla, and C.E. Hayes. Gene expression analysis suggests that 1a,25- dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis. Physiological Genomics 18:141-151 (2004).

Spach, K.M. and C.E. Hayes. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. Journal of Immunology 175:4119-4126 (2005).

Spach, K.M. and C.E. Hayes. IL-10 signaling is essential for 1,25- dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. Journal of Immunology 177:6030-6037 (2006).

Pedersen, L.B., F.E. Nashold, and C.E. Hayes. 1,25-Dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. Journal of Neuroscience Research 85:2480-2490 (2007).