Vitamin D

Steroid-related compounds such as vitamin D have many physiological functions and are used in drug therapy

Description

Steroids and steroid-related enzymes producing biologically active metabolites are vital for human physiology. Our research is focused on enzymatic processes, regulation and cellular actions involving vitamin D and other steroids. We are interested in e g vitamin D metabolism and the mechanisms whereby active vitamin D acts on eukaryotic cells. Altered vitamin D levels in plasma are linked to a number of disease conditions. It is therefore important to obtain more knowledge about the metabolism and effects of vitamin D and related compounds.

The biologically active form of vitamin D, 1a,25-dihydroxyvitamin D3, blocks cell division and increases cell differentiation. Vitamin D analogues (synthetic compounds with vitamin D-like effects) are used in treatment of psoriasis and are of interest in development of new cancer therapies. Our studies include effects of vitamin D analogues on glioblastoma, an incurable type of brain cancer. Other steroids of interest in our investigations are oxysterols (cholesterol derivatives) and sex hormones and their actions in the central nervous system.

Enzymatic processes, regulation and cellular actions involving vitamin D and other steroids

Vitamin D – bioactivation, metabolism and vitamin D-mediated effects on cellular function

This research is focused on enzymes, receptors and genes of importance for vitamin D bioactivation, metabolism and function. We study the interaction of these processes with pharmacological compounds and certain pathological cellular conditions. Vitamin D is a prohormone that is converted into the steroid hormone 1a,25-dihydroxyvitamin D by metabolic activation. This hormone exerts its biological effects mainly by binding to the nuclear vitamin D receptor (VDR). The hormone is essential for regulation of calcium levels in the body and for bone health. It is also known to block cell division and increase cell differentiation. Vitamin D analogues (synthetic compounds with vitamin D-like effects) are used in the treatment of psoriasis and are of interest in development of new cancer therapy. In addition, altered vitamin D levels in plasma have been linked to a number of different diseases. For these reasons, it is important to obtain more knowledge about the biosynthetic and metabolizing CYP enzymes and their genes as well as the receptors of relevance for various roles of vitamin D and its metabolites.

Part of this project is focused on cellular effects of vitamin D analogues in order to explore previously unknown functions of these compounds. In particular, our recent and current research interests concern five areas. 1) Vitamin D and drugs. Certain anti-viral, anti-inflammatory and anti-epileptic drugs are known to increase the risk of bone disease. Can these drugs affect the expression of the vitamin D hydroxylases in cells, and if so, by which mechanisms? 2) Vitamin D and steroidogenesis in CNS. Endogenous steroid hormones, such as estrogens and androgens, are reported to have diverse functions in the nervous system. Can vitamin D-mediated regulation of enzymes in steroidogenesis play a role in the nervous system? 3) Vitamin D and glioblastoma. Glioblastoma is the most lethal type of primary tumors in the CNS. Could vitamin D analogues be used in treatment of brain cancer? Studies include effects on proliferation, migration, invasion and metastatic potential of human glioblastoma cells. 4) Vitamin D and ER-stress. The endoplasmic reticulum (ER) is the primary location in the cell for folding of proteins. ER-stress occurs when the capacity of the endoplasmic reticulum is overloaded and may have serious consequences. ER-stress has been linked to diseases such as cancer and neurodegenerative disease. Can vitamin D metabolites affect ER-stress? 5) Vitamin D and 1,25-MARRS receptor (PDIA3). It has been reported that, in addition to the nuclear VDR receptor, another receptor protein may mediate functions of the vitamin D hormone. Can this protein play a role in expression of vitamin D hydroxylases and vitamin D-related functions in cells?

Oxysterols and other steroids - functions and roles for hormonal signaling and cellular viability

This research concerns steroids involved in hormonal signaling, sex hormone biosynthesis and brain function. The studies are focused on physiological and pharmacological control of steroid levels, effects of metabolic events and regulation of gene expression. The project concerns endogenous steroids, steroid drugs and drugs affecting steroid hormone receptors. The studies include mechanisms of importance for estrogenic and androgenic signaling. Enzymes that regulate the concentration of neuroactive steroids in the brain may be future targets for therapy of importance for abnormal cell growth, immune function or in neurodegenerative conditions. Some of our current studies involve enzymes and genes of importance for the levels of neurosteroids in neurons and glial cells. Regulation of hormone metabolism in the nervous system by endogenous steroids and pharmaceutical compounds is also studied. Steroids may affect growth and differentiation in several tissues. Thus, properties of steroids may be of interest in a wide range of normal and disease conditions, e g in neuroprotection or cancer therapy. We study effects of steroids such as enzymatically formed oxysterols (cholesterol derivatives), hormones including vitamin D and vitamin D-like compounds on cellular survival and growth. These studies particularly focus on cells of the central nervous system.

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