Biochemists search for regulatory proteins that can be targeted with new drugs
HOUSTON, July 6, 2004 -- More than 100,000 Americans suffer from the painful and debilitating genetic disorder known as neurofibromatosis, or NF, which causes tumors to grow in various types of nerve tissue throughout the body. But while the cause of the disease is well-known -- a mutation in the gene known as NF1 -- nagging questions remain about the biochemical processes that govern the illness. Why, for instance, are some patients more severely affected than others, and why do tumors tend to target different organs in different patients?
"In other studies of genetic disorders, questions like these have been answered by studying the disease in a model system, an organism that is much more genetically tractable than humans," said Michael Stern, professor of biochemistry and cell biology at Rice University. "We've developed a fruit fly model for neurofibromatosis that we're using to identify key proteins that regulate NF in humans. Ultimately, we hope drug companies can use these proteins as targets for new drugs that will limit or eliminate NF-tumor growth in people."
Stern's team has received a new four-year, $1.1 million grant from the Department of Defense Neurofibromatosis Research Program to develop the fruit fly model for neurofibromatosis and to test several key proteins it has already identified as playing a key role in NF.
For example, the fruit fly NF1 gene is very similar to its human counterpart, and Stern's previous work has shown that fruit flies lacking the NF1 gene or any of five additional genes suffer from tumors in the peripheral nerves that are similar to those found in people with NF.
Stern's group is using the grant to conduct experiments to determine whether NF1 regulates peripheral nerve growth by activating a molecule called protein kinase A. If so, the molecule, known as PKA, might be a useful drug target.
Another aspect of the research involves a search for NF-like tumor growth in dozens of strains of fruit flies, each with specific genetic mutations that cause their nerve cells to overproduce or underproduce other signaling proteins like PKA. Signaling proteins are chemical triggers that act upon the machinery of our cells. Some signaling proteins activate processes or kick them into high gear, while others may shut down those same processes.
At any given time, a cell -- be it human or fruit fly -- is subject to a cascade of information from dozens of signaling proteins that act both individually and in concert. Deciphering which triggers are vital to a process, like NF tumor growth, involves trial and error testing. When researchers find a strain of fly with NF-like tumors, for example, they conduct tests to find out which signaling proteins are being under- or over-produced.
"Imagine a complex subway system like New York's," said Stern. "Our signaling proteins are like passengers. We may know that either a lot of them or very few of them are getting to a specific destination, but we have no idea how they're getting there. So we open and close specific tunnels until we find the ones that are the most important paths."
Stern's team has identified 10 signaling proteins, including PKA, that appear to play a role in NF, and Stern suspects they'll eventually find at least twice that many are involved.
The final aspect of the DoD grant project involves the study of a fruit fly gene called "pushover" that Stern's research group discovered about five years ago. Pushover -- which draws its name from the fact that flies without the gene are easy to knock over -- creates a growth-regulating protein called Push. Stern's group is trying to learn more about how Push interacts with PKA and other compounds to regulate peripheral nerve growth.
The DoD Neurofibromatosis Research Program, the world's largest funding agency of research in neurofibromatosis, emphasizes innovative approaches to detection and treatment of the disease.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.
True courage is like a kite; a contrary wind raises it higher.
~ John Petit-Senn