The World Congress on HD - 2005
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Huntington
Society Awards Research Grants
The Research Council of the Huntington Society of Canada approved six new research grants for funding through the fall 2003 research competition. The grants were awarded through three programs: NAVIGATOR
Research Awards: Laura's
Hope Awards: Landmark
Graduate Awards: Dr.
Blair R. Leavitt People with HD have two kinds of huntingtin protein in their brain cells: the normal form of the protein, which is produced by the normal or "wild-type" HD gene that has anormal sized CAG repeat region, and the expanded or "mutant" form of the protein, which is produced by the copy of the HD gene that contains an expanded CAG repeat region. A lot of research into HD has focussed on the expanded form of huntingtin that ultimately causes cell death, but much less is known about the function of the normal protein. Interestingly, the normal form of huntingtin seems to have the opposite effect - it protects brain cells from dying. What's even more interesting is that Dr. Leavitt has shown that increasing the amount of normal huntingtin in an HD cell can block some of the toxic effects of expanded huntingtin. Dr. Leavitt plans to look more closely at how normal huntingtin works and whether it has he potential to be an effective treatment for HD. He'll examine the effects of increasing or decreasing the levels of normal huntingtin in brain cells, and try to pinpoint the specific part of the protein that prevents cell death. Next, he'll use specially bred HD mice to see whether mice with high levels of normal huntingtin have fewer Huntington's symptoms than mice with low levels of normal huntingtin. The research will take several years to complete, but it could lead to important new approaches to treating Huntington disease. Dr.
Michael Hayden Like Dr. Leavitt, Dr. Hayden is interested in how the huntingtin protein helps cells to grow and survive. He believes that one of the keys is phosphorylation - the process where a protein is modified by adding a phosphate to it. Dr. Hayden has been studying the phosphorylation of huntingtin by a specific enzyme, Akt (also known as protein kinase B). Dr. Hayden suspects that this phosphorylation process is important for proper functioning of the huntingtin protein. This leads to an important question: is the phosphorylation of huntingtin altered in the expanded form of huntingtin that is produced by the HD gene? If it is altered, this may be one reason why HD brain cells die. There's lots we need to learn. Dr. Hayden will look at a number of the factors that might influence huntingtin phosphorylation, and he'll examine how this phosphorylation affects HD brain cells. For example, he'll look at HD mice to see whether the expanded form of huntingtin is less phosphorylated than normal huntingtin. He'll confirm whether phosphorylation is necessary to protect brain cells from dying, and he'll look at how phosphorylated huntingtin interacts with other proteins in the cell. This research is still in the early stages, but it would be an exciting avenue for preventing brain cell death in HD. Dr.
Eileen Denovan-Wright It seems clear now that expanded huntingtin - the protein produced by the HD gene - is responsible for killing brain cells in people with Huntington's. So if we can find a way to prevent it from forming, we should be able to stop the disease in its tracks. That's the thinking behind Dr. Denovan-Wright's research. She believes the solution may lie in blocking something called messenger RNA (mRNA), which uses the information coded in the HD gene to build expanded huntingtin. Dr. Denovan-Wright and her colleagues have already developed two tools to do the job. One is a set of anti-huntingtin ribozymes - enzymes that specifically destroy the mRNA that produces expanded huntingtin. The other is an unusual molecule called small interfering RNA (siRNA) that can break down mRNA. In these experiments, she'll be injecting a harmless virus containing ribozymes and siRNA into the brains of HD mice. The virus will infect each cell, delivering the anti-mRNA tools in the process. Then she'll monitor the mice for signs of HD. If the hypothesis is correct, this treatment will slow down the progression of HD. And, if this works in mice, ribozymes and siRNA might be able to treat Huntington's in humans. Haibei
Hu Haibei Hu is a PhD student in Dr. Eileen Denovan-Wright's lab, and her research will also focus on ribozymes and siRNA. Although initial studies show that these molecules stop expanded huntingtin from forming by blocking the action of messenger RNA, there's still a lot we don't understand about this process. Hu hopes to fill in some of the details. First of all, she will focus on the question of doses and times. She'll work with HD brain cells to see how much ribozyme and siRNA is required to block messenger RNA, and how much time is required for them to do the job. She'll also test different types of ribozymes and siRNA to find which are most effective. In theory, blocking mRNA should prevent the next steps in the process of cell death, but it's important to see whether this really is the case. Hu will measure the level of various molecules in the cells that are afected by expanded huntingtin to make sure that ribozymes and siRNA have an impact downstream. Finally, if she gets good results at this stage, she'll repeat these experiments in an animal model - HD mice - using the ribozymes and siRNA that were most effective in the test tube. Herman
Fernandes Herman Fernandes is a graduate student who is examining a receptor in brain cell membranes - the NMDA receptor - that helps to transmit messages within the brain. Basically what happens is this: When a neighbouring brain cell is excited, it releases a messenger molecule called glutamate that binds to the NMDA receptor. The NMDA receptor responds by allowing calcium ions to flow into the cell. This generates a signal that directs the cell to perform many of its normal functions. In this way, calcium ions act as a messenger, telling the cell what to do in response to the messages that it receives. If a brain cell is affected by Huntington disease (HD), however, expanded huntingtin makes NMDA receptors overly sensitive, which means too many calcium ions flow into the cell. This triggers a sequence of events that ultimately may cause the cell to die. Herman will conduct experiments to uncover some of the details of this process and perhaps identify ways to stop it from happening. He'll compare normal cells with HD cells to see how expanded huntingtin affects the NMDA receptors, and he'll measure the changes in calcium levels inside the cell. He'll also look at how calcium levels affect mitochondria, which generate the energy necessary for cell survival. Dr.
Janice Braun Not only is the huntingtin protein involved in receiving messages from neighbouring brain cells, as Herman Fernandes is investigating, it also seems to be involved in passing along the message to other cells in the brain. Dr. Braun's lab has discovered that normal huntingtin binds to N-type calcium channels in the cell membrane. When an electric signal travels along a brain cell, these channels open, allowing calcium ions to flow into the cell. The calcium ions play an important role in helping the cell to release neurotransmitters, which relay the signal to nearby brain cells. Dr. Braun believes that when huntingtin binds to N-type calcium channels, it regulates their function, and she wants to learn more about this. She'll use a number of molecular biology and biochemistry techniques to discover details like how huntingtin binds to the calcium channels and whether any other proteins are involved. The next step will be to examine whether the expanded form of the huntingtin protein interferes with the normal function of Ntype calcium channels. If it does, it might be possible to treat HD by developing a drug that prevents expanded huntingtin from binding to these calcium channels. |
