News Archive

July 2005

December 2004

August 2004 

Oxidative Stress in Patients with Ataxia-Telangiectasia

Funded by the A-T Children’s Project, Howard Lederman, MD, PhD, Director of the A-T Clinical Center at Johns Hopkins Hospital in Baltimore, Maryland, will study how a combination of two dietary supplements, an antioxidant and a PARP-1 inhibitor can slow the neurodegeneration and aid the pulmonary problems seen in patients with A-T.

Researchers Collaborate to Generate a Rat Model for A-T

In an attempt to create an animal model that accurately represents the central nervous system dysfunction seen in patients with ataxia-telangiectasia (A-T), and which can be used to test potential treatments for the neurological abnormalities associated with this disease, two investigators have formed a collaboration to generate a rat model for A-T.

Although the mouse model of A-T mimics many of the characteristics of the human disease, it does not possess the relentless cerebellar degeneration and ataxia observed in all patients with A-T. The absence of this same type of neurodegeneration in A-T mice limits the usefulness of this animal model for the study of potential treatments for this aspect of the disease.

Therefore, Michael M. Weil, PhD from Colorado State University and Martin F. Lavin, PhD of The Queensland Institute of Medical Research in Australia, with funding from the A-T Children’s Project, are working together to make another rodent model of A-T using the rat, which may possess neurological abnormalities similar to those seen in patients.

For years mice have been genetically manipulated in order to gain a better understanding of human disease. For example, researchers have added genes to the mouse’s already existing genetic repertoire, creating so called “transgenic” mice, which produce an over abundance of a certain disease related protein. In order to study what happens when a protein is missing, as is the case in A-T, scientists can alter or mutate a particular gene in the mouse such that it no longer makes its protein product. These mice are called “knock-out” mice. The A-T mouse is an example of a knock-out mouse because it cannot make the protein (Atm) missing in ataxia-telangiectasia. Unfortunately, the technology used to create knock-out mice does not work in rats. So, although the rat is often considered a more physiologically relevant experimental model for various human diseases, researchers have not been able to genetically manipulate it like the mouse.

In 2003, however, a group of scientists published a paper describing the generation of the first knock-out rats, which fail to produce important breast cancer associated proteins. Drs Weil and Lavin will use the same technology described in this landmark paper to generate rats lacking Atm. The Atm deficient rats will be extensively studied. In addition to growth and lifespan, tumor incidence, immunological and reproductive function and radiosensitivity, neurological assessments will be made. These assessments will include examination of the cerebellum and certain behavioral tests to analyze motor function. The research performed by Weil and Lavin will hopefully produce an animal model which mimics the progressive neurodegeneration seen in humans, such that these animals can be used to study potential treatments for this devastating aspect of A-T.

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An Investigator in Rome, Italy Will Examine the Role of the
A-T Protein in Cellular Suicide

A researcher in Italy will attempt to better understand the role of the A-T protein (ATM) in programmed cell death or suicide, a process that scientists call “apoptosis.” Knowledge of how ATM regulates apoptosis will provide insight into the pathology of this disease and help researchers develop potential therapeutic interventions.

After a cell has incurred damage to its genetic material (or DNA), a series of internal events will take place to stop cell division and growth and allow DNA repair to take place. Alternatively, the cell may undergo programmed cell death and be eliminated (if, for example, the amount of DNA damage is too great to repair). If neither of these events takes place, then the cell may retain the damaged DNA and transform into a cancer cell. Importantly, the ATM protein coordinates a cell’s response to a certain type of DNA damage. However, the precise mechanism by which a cell chooses between repair and apoptosis following damage is not completely understood.

To help elucidate the role of ATM in the apoptotic process, Daniela Barilá, PhD, Assistant Telethon Scientist of the Delbecco Telethon Institute at the University of Tor Vergata in Rome, Italy has been awarded a grant by the A-T Children’s Project. Dr. Barila’s laboratory will investigate the role of ATM in death-receptor induced apoptosis. This form of programmed cell death results when a specific protein binds a special receptor on the cell’s surface (a so-called “death” receptor). This interaction, in turn, signals a cascade of events to occur within the cell, ultimately resulting in its demise. Moreover, this pathway plays an important role in the development of the immune system, which is severely affected in A-T.

Dr. Barilá and her team have obtained evidence that the ATM protein may be turned on following activation of the death receptor pathway. Dr. Barila’s laboratory will investigate this finding further and attempt to determine which proteins are targeted by ATM during death receptor mediated apoptosis. In addition, Dr. Barilá and her lab will observe how this type of apoptosis occurs in cells which are deficient in ATM protein. “This project, “states Dr. Barila, “will make a significant contribution to understanding the molecular basis of A-T pathology.” Therefore, Dr. Barila’s A-T Children’s Project funded research contributes to the quest for potential drug targets for A-T.

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