Our lab is, in general, interested in cellular signaling cascades in the brain and its interaction with periphery tissues. We are, particularly, focusing on two areas right now.
1. Energy Homeostasis, Food Intake, Obesity and Metabolic Syndromes
a) Nutrients (amino acid, glucose and lipid)-Mediated Signaling.
The ability to sense availability of nutrients and to regulate energy balance is fundamental process of all the living creatures. Obesity is an increasingly common health problem in the U.S. and throughout the developed world. Approximately two-thirds of the U.S population is currently obese or overweight. It has been acknowledged as the second leading cause of death, behind smoking. Obesity has been linked to diabetes, hypertension, cardiovascular disease, cancer, and a myriad of other health problems. Obesity results from disturbed energy balance, where energy intake (i.e. feeding) chronically exceeds total energy expenditure. Hene one of the key processes in the energy balance is to sense and respond to changes in nutrients (e.g amino acids, glucose, or lipid). A flurry of research activities has identified many genetic or biochemical components for nutrients sensing and has elucidated their roles in obesity and obesity-associated diseases. However the exact mechanism underlying development of obesity and interplay between numerous components are poorly understood. One of the primary goals in my laboratory is to understand how our body senses and responds to different levels of nutrients such as glucose or lipid, and how different pathways cross talk to each other.
b) Antipsychotic Drugs-Mediated Obesity.
Antipsychotic drugs relieve symptoms of schizophrenia as well as manic-depressive illness. The first generation drugs, however, were ineffective in many patients and failed to alleviate features such as emotional withdrawal reflecting the “negative” symptoms of schizophrenia. A new generation, “atypical” antipsychotic drugs, help non-responders, ameliorate negative symptoms, have fewer side-effects and so have emerged as some of the most widely used of all drugs. However, their use has been hampered by severe weight gain elicited by some of those agents, sometimes doubling patient weights and with no clear cut explanation. We have found that the drugs that cause weight gain potently and selectively activate the enzyme AMP-kinase in the hypothalamic area of the brain in discrete nuclei which regulate eating behavior. This activation occurs secondary to the drugs’ blocking the H1 receptor for histamine, which, besides its roles in allergy, is a neurotransmitter in the feeding centers of the hypothalamus.
2. Iron in the Brain
a) Oxidative Stress-Mediated Neurodegeneration.
Iron metabolism in the brain is similar to that of the rest of the body in that all of the major proteins associated with regulating iron in systemic circulation arealso expressed in the central nervous system (CNS). However, iron acquisition by the CNS is problematic as the CNS is functionally separate from systemic circulation by the blood-brain barrier (BBB) and the blood-cerebrospinal barrier, and thus, cannot acquire iron from circulating serum Transferrin. Nevertheless, iron is abundant in the brain and has distinct regional and cellular patterns, being highest in the basal ganglia at a concentration equivalent to that of the liver. Even though we made a huge progress in understanding iron homeostasis in systemic levels due to the discoveries of many proteins in iron metabolism recently, virtually no studies have been done how brain iron homeostasis is regulated mainly due to heterogeneous cell types in the brain. Hence, most of the studies of iron in the brain have centered around its pathophysiological properties and participation in various neurodegenerative diseases. Iron accumulates normally as a result of aging. However, when iron is present in excess, it can produce reactive oxygen species, such as hydroxyl radicals, via Fenton chemistry, which can augment neuronal injury. These hydroxyl radicals are highly reactive and can attack proteins, lipids and DNA, forming cross-links and inhibiting function. We have identified a cascade whereby glutamate-NMDA receptor activation via NO and Dexras1, a novel small GTP binding protein, physiologically stimulates DMT1, the major iron importer. We are investigating the role of Dexras1 in brain iron homeostasis/oxidative stress on cellular and systemic levels in relation to neurodegeneration.
b) Iron/Stress, Neural Cirtuit and Behavior.
The brain’s iron requirement is relatively high, consistent with its high consumption of oxygen. The ability of the brain to store readily bioavailable iron is essential for normal brain function because both iron deficiency and excess in the brain have serious neurological consequences. Our recent finding on NMDA-mediated iron trafficking is the first demonstration to link neurotransmission and active regulation of iron trafficking in the brain, suggesting that iron can be an active modulator in the brain. Moreover, iron imbalance is suggested to be linked to mental illnesses such as schizophrenia, depression or attention deficit and hyperactive disorders. Interestingly, iron is known to regulate the activities of many enzymes which control the synthesis of neurotransmitters and in particular catecholamine. As such, iron helps to regulate the activity of the neurotransmitter dopamine, which probably accounts for the association of iron deficiency with several neurological problems. Moreover, iron accumulation plays a key role in aging and the decline in cognitive functions associated with neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease. Hence simple iron supplementation may possibly lead to deleterious effects. Most recently, Blakely’s group showed that the level of brain iron is enhanced in mice with a defect in serotonin transporter protein, whose variations have been linked to many psychiatric diseases such as depression, autism, alcoholism and obsessive-compulsive disorder. While there have been significant advances made in our understanding of the cellular and molecular mechanisms that regulate iron absorption, transport, storage, and utilization in the peripheries, the effects of iron in brain development and its function is not fully understood. Considering its abundance in the brain and its association with neurotransmitters, it is reasonable to speculate that iron can play a pivotal role in brain development and consequently behavior. We attempt to trace the movement of iron throughout life in health and disease comparing with changes in neural circuits and behavior. This work is done in collaboration with Dr. Greg Carlson. Our studies will elucidate the pathophysiologic as well as physiologic role of iron in brain development and its function.
Our lab utilizes molecular, cellular, biochemical techniques as well as chemical genetics in tissue culture, primary cell and animal models to address these issues.