Yan Chun Li, Ph.D.

Function of the Vitamin D Endocrine System

Research Summary

The main research interest of my laboratory concerns vitamin D/vitamin D receptor and the vitamin D endocrine system. We utilize transgenic and gene knockout mouse models, in combination with cellular and molecular approaches, to investigate the physiological functions of this endocrine system and the underlying molecular mechanisms. Our current research focuseson several areas.

The main research interest of my laboratory concerns vitamin D/vitamin D receptor and the vitamin D endocrine system. We utilize transgenic and gene knockout mouse models, in combination with cellular and molecular approaches, to investigate the physiological functions of this endocrine system and the underlying molecular mechanisms. Our current research focuseson several areas.

Calcium homeostasis. This project studies the role of vitamin D in the regulation of transcellular calcium transport. We have shown that vitamin D receptor inactivation leads to severe hypocalcemia in mice due to impaired calcium reabsorption in the kidney, which is correlated with a drastic reduction in renal calcium-binding protein (calbindin-D9k) expression. To confirm our finding, currently we are investigating the possibility of rescuing the hypocalcemia by targeting calbindin-D9k expression to the kidney through adenovirus-mediated gene transfer and by kidney transplantation. Meanwhile, we are also studying the molecular mechanism whereby vitamin D regulates calbidnin-D9k gene expression by analyzing thecalbindin-D9k gene promoter.

Hypertension and volume and electrolyte homeostasis. This project investigates the role of vitamin D in the regulation of the renin-angiotensin system. We have shown that vitamin D acts as a physiologically important negative regulator of renin gene expression, and inactivation of the vitamin D receptor leads to over-stimulation of the renin-angiotensin system and hypertension in mice. Currently, we are studying the renin gene promoter in order to elucidate the molecular mechanism of vitamin D suppression of the renin gene. We are also screening vitamin D analogues for their renin-suppressing activity, hoping to develop new anti-hypertension drugs. Most recently, we are expanding our research on potential vitamin D target genes in the kidney identified by DNAmicroarrays.

Lipid metabolism and energy homeostasis. This project explores the role of vitamin D in lipid metabolism and energy homeostasis. By using transgenic mouse models, we are investigating the effect of lack-of-function and gain-of-function of the vitamin D receptor on lipid metabolism and energy homeostasis. We are also using in vitro cell culture systems to study theeffect of vitamin D on adipogenesis.

Keratinocyte and hair cycle regulation. This project investigates the role of vitamin D in the regulation of keratinocyte functions and the ligand-independent mechanism of vitamin D receptor regulation of the hair growth cycle. We have shown that vitamin D receptor is required for the initiation of postnatal hair cycles, and vitamin D receptor inactivation leads to development of alopecia (hair loss). In our future studies we will use DNA microarray technology to identify vitamin D target genes in the skin that are important for hair growth. We are also investigating the potential molecular interplays between the vitamin D receptor, retinoid X receptor and hairless gene in hair cycle control. Another research focus is vitamin D regulation of pro-inflammatory cytokine productions in keratinocytes, as these cytokines are important for the development of hyperproliferative skindiseases such as psoriasis.

Selected Papers

Li YC (2003). Vitamin D regulation of the renin-angiotensin system. J. Cell. Biochem. 88: 327-331.

Wali R, Kong J, Sitrin MD, Bissonnette M, Li YC (2003). The vitamin D receptor is not required for the rapid actions of 1,25-dihydroxyvitamin D3 to increase intracellular calcium and activate protein kinase C in mouse osteoblasts. J. Cell. Biochem. 88: 794-801.

Kong J, Li YC. (2003). Effect of ANG II type I receptor antagonist and ACE inhibitor on vitamin D receptor-null mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285: R255-R261.

Li X, Zheng W, Li YC. (2003). Altered gene expression profile in the kidney of vitamin D receptor knockout mice. J. Cell. Biochem. 89: 709-719.

Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J. (2004). Vitamin D: A negative endocrine regulator of the renin-angiotensin system and blood pressure. J. Steroid Biochem. Mol. Biol., 89-90:387-392.

Bolt MJG, Liu W, Qiao G, Kong J, Zheng W, Krausz T, Cs-Szabo G, Sitrin MD, Li YC (2004). Critical role of vitamin D in sulfate homeostasis: Regulation of the sodium-sulfate co-transporter by 1,25-Dihydroxyvitamin D3. Am. J. Physiol. Endocrinol. Metab. , 287:E744-E749.

Xiang W, Kong J, Chen S, Cao L-P, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC. (2004). Cardiac Hypertrophy in Vitamin D Receptor Knockout Mice: Role of the systemic and cardiac renin-angiotensin systems. Am. J. Physiol. Endocrinol. Metab., in press.

Zheng W, Xie Y, Li G, Kong J, Feng JQ, Li YC. (2004). Critical role of calbindin-D28k in calcium homeostasis revealed by mice lacking both Vitamin D receptor and calbindin-D28k. J. Biol. Chem., in press