Room: 507B, BMSB Office: 2609 6780 Email: yake@cuhk.edu.hk

KE, Ya

Assistant Professor

B.Med. (1997) Suzhou Medical College
Ph.D. (2003) The Hong Kong Polytechnic University

Physiology and pathophysiology of brain iron metabolism
Abnormally increased iron in affected brain areas has been demonstrated in neurodegenerative disorders. A number of studies, especially the new discovery of mutations in the genes associated with brain iron metabolism, lend favor to the hypothesis that the increase in iron in the brain is an initial cause of neuronal death at least in some neurodegenerative disorders. However, very little is known about the mechanisms involved in brain iron homeostasis and therefore a key question of why iron is abnormally increased in the brain has not been answered. A full understanding of the physiologic aspects of brain iron metabolism is fundamental and critical for elucidating the pathophysiological mechanisms responsible for the excess iron accumulation in the brain. The topics I am interested in include 1. cellular and regional distribution, expression control, function and the associated mechanism of iron metabolism proteins in the brain; 2. mechanisms of iron transport across the blood-brain barrier (BBB); 3. identification of the unknown genes of iron metabolism and mutations associated with neurodegenerative diseases.

Application of hepcidin and transplantation of stem cells in the treatment of iron-associated neurodegenerative diseases
New findings showed that increase in brain iron is an initial cause of some neurodegenerative diseases. The application of agents to decrease brain iron will therefore be an effective therapeutic approach. Recent studies demonstrated that hepcidin, a newly discovered iron regulating hormone, plays a central role in body iron homeostasis. We have demonstrated that the brain has the ability to express hepcidin. Our preliminary study also showed that injection of hepcidin into the brain can lead to a decrease in iron content of PD rat brain This showed that hepcidin might be a right agent to reduce iron in the brain. I am also interested in the effect of transplantation of stem cells from different sources and/or hepcidin on the recovery of CNS function in the iron-loading animal models of PD.

Pathogenesis of some iron-associated disorders
It is now well established that excessive iron-mediated injury plays an important role in the development of a number of cardiovascular diseases. Extensive clinical, epidemiologic and basic studies have also suggested that excess iron may contribute to the occurrence and complication of type 2 diabetes and its complications. However, it is currently unknown how iron increases to a pathological level in these tissues. I am interested in the mechanisms involved in the over-accumulation of iron in these disorders and the roles of hepcidin and Hemojuvelin (HJV) in heart iron homeostasis.

Selected Publications:

• Chang YZ, Qian ZM, Du JR, Ho KP, Zhu L, Xu Yj, Li LZ, Wang CY, Wang Q, Ge XH, Niu LJ, Lin Li, Ke Y* (2007) Development and iron-dependent expression hephaestin of in different brain regions of rats. Journal of Cellular Biochemistry In press

• Chang YZ, Qian ZM, Du JR, Zhu L, Xu Yj, Li LZ, Wang CY, Wang Q, Ge XH, Ho KP, Niu LJ, Ke Y* (2007) Ceruloplasmin expression and its role in iron transport in C6 glioma cells. Neurochemistry International 50: 726–733

• Gao J, Zhu Z, Ding Z, Ding HQ, Qian ZM, Zhu L, Ke Y* (2007) Vulnerability of neurons with mitochondrial dysfunction to oxidative stress is associated with down-regulation of thioredoxin. Neurochemistry International 50(2):379-385

• Chang YZ, Ke Y, Du JR, Ho KP, Zhu L, Xu YJ, Wamg Q, Li LZm Wang CY, Qian ZM (2006) Increased DMT1 expression might be associated with the neurotoxicity of L-DOPA. Molecular Pharmacology 69(3): 968-974

• Ke Y, Ho KP, Du JR, Zhu L, Xu YJ, Wang Q, Wang CY, Li LZ, Ge XH, Chang YZ, Qian ZM (2006) Role of soluble ceruloplasmin on iron uptake by midbrain and hippocampus neurons. Journal of Cellular Biochemistry 98(4): 912-919.

• Chang YZ, Qian ZM, Wang K, Zhu L, Yang XD, Du JR, Jiang L, Ho KP, Ke Y (2005) Effects of development and iron status on ceruloplasmin expression in rat brain. Journal of Cellular Physiology 204(2): 623-631

• Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM (2005) Iron-independent and age-dependent expression of the two mRNA isoforms of divalent metal transporter 1 in different brain regions of rats. Neurobiology of Aging 26(5): 739-748

• Du XL, Ke Y, Yuan L, Li R, Wang K, Ho KP, Qian ZM (2004) Apotransferrin is internalized and distributed same as holotransferrin in K562 cells. Journal of Cellular Physiology 201: 45-54

• Ke Y, Qian ZM (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. The Lancet Neurology 2(4): 246-253

• Ke Y, Chan YY, Zhang YZ, Duan XL, Ho KP, Jiang DH, Wang K, Qian ZM (2003) Post-transcriptional expression of DMT1 in the heart of rat. Journal of Cellular Physiology 196(1):124-130