The research builds on genetic studies conducted over the past decade by scientists around the world and at Texas Biomed that have helped identify large numbers of differences in the sequence of the human genome that are contributing to a wide range of diseases. The challenge that remains is understanding how these changes in the DNA sequence specifically affect the cells in the body, and lead to obesity, diabetes, heart disease or even neurological disorders such as Parkinson’s disease. Once scientists understand the underlying mechanisms, they may be able to develop new therapies and actually improve treatment for these diseases.
To accelerate this process, the National Institute for General Medical Sciences (NIGMS) of the National Institutes of Health requested proposals from researchers to develop novel and innovative approaches that will help decipher the function of these specific genome sequence changes, and now awarded Michael Olivier, Ph.D., Texas Biomed’s newest recruit to the Department of Genetics, a new 4-year grant to develop and implement such technologies. His laboratory specifically focuses on developing new ways to study how proteins – little machines in cells that do everything, from producing energy to sending signals to other cells to recognizing and responding to challenges such as fat in the diet – interact with the DNA in our cells to regulate the expression of genes.
Genes can be turned on or off, depending on whether a cell needs more or less of a specific protein, and this complex regulation is influenced by a large number of other proteins that bind to the DNA and regulate it. These regulatory proteins bind to specific sequences in the DNA, and if this sequence is changed in an individual, that particular protein may no longer bind as efficiently. The result is that a nearby gene is regulated differently in a person with this specific change in the DNA sequence.
“Obviously, this complex regulation of genes requires a large number of different proteins, and many of them we do not even know yet,” Olivier said. “This is why we are trying to develop a method that allows us to look at one specific piece of DNA, such as one gene, and to identify all the proteins that are bound to that particular sequence.”
Once the sequence has been isolated, the bound proteins can be identified by mass spectrometry. In collaboration with Joanne Curran, Ph.D., Harald Göring, Ph.D., and John Blangero, Ph.D., in the Texas Biomed Department of Genetics, and Dr. Lloyd Smith, Professor of Chemistry and Director of the Wisconsin Genome Center at the University of Wisconsin, Madison, Dr. Olivier will exploit this new methodology to examine cells from members of the San Antonio Family Study. Here, they will identify proteins that regulate genes important in the regulation of cholesterol and other risk factors for heart disease.
Previous studies have helped identify changes in the DNA sequence of study participants that raise their cholesterol levels, which increases their risk for heart attacks or strokes. This new study will now identify how these sequence changes modify the regulation of specific genes, and which proteins are important in that regulation.
“Identifying the proteins that are important for this regulation of genes will not only help us understand how these sequence changes lead to higher cholesterol levels in these participants, it will also help us to identify new drugs that may help correct these changes, and help reduce the risk for a heart attack or stroke,” Olivier said.
For now, however, his lab is focusing on developing the necessary protocols and methods so that they can begin these investigations – a challenging effort requiring a wide range of expertise in his group, from chemistry to genetics to cell and molecular biology. And with the new support from the NIH, they hope to be able to develop and apply these new methodologies quickly so that they can be used to help understand how the human genome works, and how the sequence differences in it affect disease risk.