Year: 2005

Proteins called calcium channels regulate when and how much calcium gets into nerve cells. In humans, calcium channels control a variety of normal physiological responses including muscle and heart contraction, hormone secretion, and the way neurons transmit, receive and store information in the brain. When too much calcium enters cells through calcium channels, a number of disorders can result, including congenital migraine, angina, epilepsy, hypertension and stroke. Michael Hildebrand is studying the interactions between the most recently identified family of calcium channels (T-type channels) and a membrane receptor called the mGluR receptor. This receptor is activated by the neurotransmitter glutamate and triggers internal chemical signals within neurons. T-type channels and mGluR receptors are highly expressed in the same cell types in various brain areas and both proteins are shown to be involved together in various physiological processes. Michael’s research will specifically contribute to better understanding of how mGluR receptors are able to selectively turn on and off specific members of the T-type calcium channel family. Results will lead to further understanding of brain development, normal brain functions such as learning and memory, and abnormal functions such as epilepsy.

Depression is a devastating mental disease that affects up to 10% of the population. Its neurobiological basis is unknown. Traditionally, depression was thought to be caused by a deficiency in the monoamine neurotransmitter molecules, such as serotonin. Based on that assumption, antidepressant drugs were developed to prevent the breakdown of monoamines. However, recent advances in neuroscience have demonstrated that the effects of antidepressants on monoamine levels are immediate, whereas actual changes in mood take many weeks, which means the ability of antidepressants to effectively treat depression is likely due to long term changes in other systems. There is growing evidence linking depression to the endocannabinoid system – a group of molecules and their receptors that act as a modulatory system, fine-tuning the body’s responses to a variety of stimuli. Various studies have suggested that endocannabinoids may be reduced in depression and that use of antidepressants may act to increase them. Mathew Hill is examining the relationship between endocannabinoid and antidepressants. He is specifically interested in determining if increasing endocannabinoid activity is a common response to all types of antidepressants; if changes in the endocannabinoid system are required for antidepressants to work; and if increasing endocannabinoid activity alone is sufficient to elicit an antidepressant response. Results from his study will contribute to a better understanding of the neurobiology of depression and ultimately may lead to a new class of antidepressants.

The complex arrangement of carbohydrates that cover the surfaces of cells is known to play a key role in biological processes ranging from cellular recognition to gene regulation. Changes in the composition of these carbohydrate structures are linked to the onset of many diseases, including the proliferation of cancer cells and compromised immune function. Research suggests that these changes are often associated with elevated activities of the enzymes responsible for sugar placement. As such, these enzymes (glycosyltransferases) represent an attractive drug target for the treatment of many human diseases. Unfortunately, multiple enzyme forms for a given sugar transfer are encoded by the human genome and the role that individual genes play in both normal and pathological cell surface modification remains largely unknown. Luke Lairson’s goal is to identify the small molecules that inhibit the activity of a class of glycosyltransferases known as sialyltransferases. These enzymes are responsible for adding a particular type of sugar known as sialic acid (known to play a key role in many types of cancer) to cell surfaces. Luke hopes that identifying these small molecules will serve as a potential starting point for the development of a new class of anti-cancer drug. His results may also be used to develop a technology for the identification of individual gene products responsible for the placement of particular sugars in both normal and diseased cells at a given point during development.

Bilirubin is an abundant, reddish-yellow bile pigment found in mammalian tissues and serum. The pigment has long been regarded as simply a cytotoxic waste product that needs to be excreted, as bilirubin in high concentrations can cause neurological damage. In recent years, however, increasing evidence suggests that bilirubin may also have functional importance. In vitro studies have demonstrated that bilirubin is an antioxidant substance. Other studies indicate that bilirubin may be capable of modifying or regulating immune functions. At present, however, the potential biological activities and physiological role of bilirubin is not well understood. Yingru Liu is studying the antioxidant effect of bilirubin, and exploring other physiological functions that bilirubin may also possess. Specifically, he is using an animal model to investigate the potential protective role of bilirubin as it relates to multiple sclerosis, a disease in which oxidative stress by free radicals and immunological factors play important disease-causing roles. His work may characterize the bile pigment system as an attractive target for drug therapy in multiple sclerosis. In addition, his research may have an impact on guidelines for treatment of an excess of bilirubin (such as neonatal jaundice and physiological hyperbilirubinemia). It may also confirm the need and potential methods of treating abnormally low levels of bilirubin.

Bone marrow contains cells which infrequently contribute to the repair of numerous tissues and therefore holds tremendous potential for regenerating damaged tissues in adults. Conceivably, a simple bone marrow transplant could one day facilitate treatment of a variety of degenerative conditions such as muscular dystrophy or Alzheimer’s disease. However, researchers first must discover which bone marrow derived cells are involved as well as the mechanisms which guide the repair processes in order to increase its efficency to therapeutic levels. Michael Long is investigating this phenomenon utilizing bone marrow transplantation in mice. His research aims to identify the lineage and mechanism responsible for the generation of new tissue from bone marrow. Ultimately, Michael’s research will contribute to the development of novel therapeutic strategies that efficiently restore organ and tissue function.