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Current Studies

Most recently, we have defined and continue to investigate key aspects of the molecular mechanisms through which the vitamin D hormone autoregulates the expression of its own receptor in certain tissues, and modulates the expression of a wide variety of additional genes whose protein products are integral to the biologic actions of vitamin D in numerous target tissues. These studies have been made possible as a result of newly developed methods whereby interactions of the VDR with target genes and, most importantly, the transcriptional consequence of those interactions can be assessed within intact living cells both in culture and in vivo. This approach, termed chromatin immunoprecipitation-DNA microarray analysis or ChIP-chip is an enormously powerful methodology which can be applied to the study of single genes, multiple genes, or to the complete genomes of a number of different organisms including those of mice and humans. These types of studies, coupled with a more focused examination of isolated regulatory regions and/or specific gene loci, and linked directly to genetic and transgenic animal studies, promise to further unlock the complex details that govern the mechanisms whereby the vitamin D hormone and its receptor regulate the transcription of genes involved in not the biology of calcium and phosphorus control, but that of skin, the immune system, and cellular growth and differentiation as well. Thus, we are poised to advance to a significant degree our understanding of how the vitamin D hormone 1,25(OH)₂D₃ operates in diverse tissues and at target genes to regulate important biological processes.

Therapeutic Possibilities

The impact of the vitamin D hormone on not only the skeleton, but at the immune system and on aberrant cell growth has led to the possibility that the hormone or synthetic versions of this molecule could be therapeutically useful for the treatment of a wide variety of diseases, not the least of which is cancer. As a result, a better understanding of how vitamin D operates in these conditions and which target genes are involved is likely to prove useful in the further development of efficacious drugs. One example is the capacity of 1,25(OH)₂D₃ to regulate the expression of RANKL, a gene whose TNF-like product is responsible for the production and activation of bone cells that function exclusively to resorb the skeleton. Indeed, the over-expression of this factor is often associated with osteoporosis and appears to be involved in virtually all diseases of low bone mass. RANKL also provides a mechanism for facilitating tumor cell growth following metastatic cell migration from numerous primary cancers. Thus, an understanding of how RANKL is regulated by the vitamin D hormone and other cellular factors, a project with which we are involved, could well lead to the development of an inhibitor whose actions might reduce the expression of RANKL from certain cell types. This inhibition is likely to limit not only the level of bone resorption, but the capacity of the skeleton to provide a fertile environment for further metastatic tumor growth.

Sex Steroid Hormones

Steroid hormones such as the estrogens and androgens, whose primary roles are to control reproductive functions, also influence the mineral status of higher organisms. Thus, they contribute significantly to the regulation of skeletal bone mass by virtue of their ability to protect the skeleton from resorption. Accordingly, the loss of estrogens and/or androgens, a phenomenon that occurs in advanced age in humans as a result of either female menopause or male andropause, results in a striking increase in bone resorption, osteoporosis and eventually bone fractures. The protective effects of estrogens and androgens or their numerous analogs at the skeleton highlight their utility as perhaps the most effective current therapy for preventing bone loss in elderly postmenopausal women. In this area, we seek to extend our basic understanding of key target genes that are regulated in bone cells by these two hormones and the mechanisms that underlie their regulation. We anticipate that better drugs can be designed and developed based upon this information, and then utilized to treat more effectively bone-debilitating diseases.

Models Used

1.	Primary cells in culture
2.	Cultured cell lines
3.	Animal models (normal, genetic and transgenic mouse and rat models)

Current Laboratory Projects

1.	Determination of fundamental mechanisms of transcriptional control.
2.	Development of overarching principles for vitamin D hormone action in bone, intestine, and tumor cells using methods amenable to genome-wide analyses.
3.	Identification of genes that represent target of activity for the vitamin D, estrogen and androgen hormones in skin, the immune system, and in tumor cells.
4.	Definition of detailed molecular mechanisms whereby certain target genes are regulated by the vitamin D, estrogen and androgen hormones.
5.	Development of unique reporter genes that can be introduced into mice to study feature of tissue-specific gene expression and regulation.
6.	Determine mechanisms of action of unique vitamin D, estrogen and androgen analogs with potential therapeutic utility.

Future Goals

To better understand the intricate details of vitamin D, estrogen and androgen hormone action at the cellular level, thereby facilitating the design and development of synthetic versions of these natural hormones with broad therapeutic potential.