Net Results Express Title

October 2005

Inside this issue...

New Research

Telomerases
Behaving
Badly

Behind the
(Caspase-)Eight Ball

Molecule Required for Immune Cell Survival

Molecule
First in Line

OCD-Related
Neurons Pinpointed

Breaking News

UHN Researcher
Named to CRC

UHN Researchers Honoured

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uhnresearch.ca

New Research Breakthroughs at UHN

    Telomeres: The Burning Fuses of Cell Division

      Drs. John Dick and Lea Harrington have discovered regulation of telomere length, a process which is often disrupted in cancer, may be more complex in human blood-forming cells than in other cell types.

      Telomeres—specialized structures at the ends of chromosomes that prevent DNA damage—are shortened each time a cell divides. They are partially—but not completely—restored by an enzyme called telomerase. When telomeres are shortened beyond a certain limit, the cell's lifespan expires, triggering cell death.

      In most cell types, increasing telomerase activity will prevent cell death, but the researchers have discovered that this is not the case for the blood-forming, or hematopoietic, cells involved in leukemia. This suggests that increased telomerase activity may have biological effects on leukemic cell growth that are not linked to telomere elongation.

      “Changes in telomerase activity may be an early step in leukemia. Investigating how telomere length is stabilized differently in these blood-forming cells may lead to therapeutic targets specific to leukemia,” says Dr. Dick.

      Proc Natl Acad Sci USA 2005 Oct 4; 102 (40):14398–14403.
      [PubMed abstract]
      Research supported by Canadian Institutes of Health Research, National Cancer Institute of Canada, Canadian Cancer Society and Canada Research Chair.

    Immune Disorders: Behind the (Caspase-)Eight Ball

      A team led by Dr. Razq Hakem has added new evidence for the role of caspase-8 in immune regulation, which may shed light on why caspase-8 deficient patients have symptoms of immune deficiency, as well as autoimmunity.

      Dr. Hakem found that mice that lack caspase-8 have abnormally low levels of immune cells when they are young and abnormally high levels of immune cells as the mice age. These results suggest that caspase-8 is involved in keeping the production and destruction of immune cells balanced to effectively fight infection.

      “We have made a connection between caspase-8 function and how it relates to disease,” says Dr. Hakem. “Now, we can use this animal model to evaluate strategies for therapy and prognosis for caspase-8 deficient patients,” says Dr. Hakem.

      J Exp Med. 2005 Sep 19;202(6):727-32. [PubMed abstract]
      Research supported by Canadian Institutes of Health Research and the Terry Fox Foundation.

    cFLIP-Deficient Mice Flop at Immune Cell Survival

      Researchers Drs. Wen-Chen Yeh, Razq Hakem, Tak Mak and Pam Ohashi have discovered that cFLIP is critical for maintaining immune cell survival, a process that, when unregulated, may lead to cancers of the immune system such as lymphoma.

      By developing a mouse model that lacked cFLIP, the researchers found that mice were unable to produce new immune cells and that, as a result, the mice had severely reduced levels of immune cells in the thymus, lymph nodes and spleen. These findings are similar in mice that lack caspase-8, the factor mentioned in the previous story, suggesting that these molecules may be linked.

      “Our results show that cFLIP is not only important in immune cell development, but also in immune cell survival,” says Dr. Yeh. “It is possible that cFLIP may be a potential target for stopping uncontrolled growth of immune cells.”

      J Exp Med. 2005 Aug 1;202(3):405-13. [PubMed abstract]
      Research supported by the Terry Fox Program and the Canadian Institutes of Health Research.

    Molecule First in Line for Gene Expression

      Dr. Rod Bremner has shown that a factor called BRG-1—which is thought to have a role in cancer suppression—is necessary for cellular changes following an immune response.

      Transcription is one of the first steps in gene expression and it involves a stepwise recruitment of molecules. All previous clues pointed to a different molecule as the first molecule required for transcription regulated by the immune system. Dr. Bremner has suprisingly revealed that BRG-1 is the first to arrive.

      “Tumours often contain mutations in the BRG-1 gene,” says Dr. Bremner. “By evaluating the role of BRG-1 we can begin to understand more about immune regulation and how it prevents—or fails to prevent—cancer development.”

      Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14611-6. [PubMed abstract]
      Research supported by the National Cancer Institute of Canada and the Canadian Cancer Society.

    Decisions, Decisions: Precise Recording Pinpoints Sources of Neurological Conflict

      Drs. Karen Davis, Andres Lozano, Mary Pat McAndrews, Jonathan Dostrovsky and William Hutchinson, Erich Richter and graduate student Keri Taylor have reported that results from a technically sophisticated method called single neuron recording may have implications for treatment of obsessive-compulsive disorder (OCD).

      The researchers tested OCD patients with several variates of the Stroop task while measuring the activity of single neurons in a part of the brain called the caudal anterior cingulate cortex (cACC) during therapeutic surgery. The task requires an individual to assess one aspect of a word list (i.e., the number of words) under conditions of cognitive and/or emotional conflict due to the content of the words.

      “We have identified populations of cACC neurons that behave differently depending on the salience or type of conflict imposed by task,” says Dr. Davis. “Since diseases such as OCD may be related to how these types of neurons respond, we may be able to pinpoint these neurons surgically to treat OCD patients.”

      J Neurosci. 2005 Sep 14;25(37):8402-6. [PubMed abstract]
      Research supported by Ontario Mental Health Foundation and the Canada Research Chair Program.

Breaking News from UHN Research
    UHN Researcher Named to Canada Research Chair

      UHN Research congratulates Dr. Karen Davis (TWRI/TWH), who has been awarded a renewal of her Tier II Canada Research Chair in Brain and Behaviour. Dr. Davis' research involves studying pain and attention using brain imaging, as well as behavioural and electrophysiological techniques, to develop new diagnostic tools and treatments for brain disorders.


    UHN Researchers Recognized for Remarkable Achievements

      Drs. Ernest McCulloch, James Till (OCI/PMH) and Tak Mak (CFIBCR/OCI/PMH) represented three of the four top Canadian scientists honoured for their contributions to cancer research at a special dinner in Toronto on October 18. The event was co-hosted by the Canadian Institutes of Health Research and the Ontario Cancer Research Network.

Research Fact
Upcoming Events
    Research has a full calendar for October/November. Among the upcoming events are:
      • October 27/28: Annual visit of the UHN International Research Advisory Board
      • October 31: UHN's annual Research Day
      • November 9/10: Opening Symposium, UHN Research Programs at Toronto Medical Discovery Tower, hosted by UHN Global Ventures

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