Four researchers at UT Health Center receive grants worth more than $4.7 million

Thursday, July 19, 2007

Four researchers at The University of Texas Health Science Center at Tyler recently received grants worth a total of more than $4.7 million.

The topics of these grants range from how genetic data about drug addiction might be used in the criminal justice system to developing new drugs to treat breast cancer.

The researchers are T. Howard Stone, JD, LLM, associate professor of bioethics; Malini Rajagopalan, Ph.D., associate professor of biochemistry; Usha Pendurthi, Ph.D., associate professor of molecular biology; and Vijay Rao, Ph.D., professor of biochemistry.

Dr. Stone received a $1.757 million, four-year grant from the National Institutes of Health to study the legal and ethical ramifications of using genetic information about drug addiction in the criminal justice system.

This is the first project of this type funded by NIH, Dr. Stone said. About 1 or 2 percent of the NIH funds that support genetic research are used to study the ethical, social, and legal consequences of such research.

One area of study is the use of genetic information in non-health-care settings. For example, genetic information from people addicted to drugs could be used by the criminal justice system to identify persons who may be vulnerable to drug use disorders over their lifetime.

In addition, genetic information could be used to determine the length or imposition of prison sentences and to regulate the system’s treatment of people with addictions.

“As the science of drug addiction advances, courts and criminal justice systems will want to use this new information. We have the opportunity to examine how this information might be used, so that the criminal justice system can respond responsibly and develop policies for its use,” Dr. Stone said.

The first aim of this four-year project is to inventory and analyze all current laws that use drug addiction information for criminal justice purposes, he said. During the grant’s first year, researchers will create a publicly accessible online database of these laws.

In the second year, researchers will conduct focus groups and surveys involving the stakeholders and shapers of public opinion, policy, and criminal justice practice in this area, Dr. Stone said.

These will include judges who preside over special drug courts, correctional officials, and addiction and drug treatment professionals. The purpose is to measure the current knowledge, attitudes, and information needs of these stakeholders regarding drug addiction science, including genetics, he said.

In the third year, major stakeholders will discuss and review the issues and the study’s findings, then develop appropriate responses, Dr. Stone said.

In the fourth year, materials, including training modules and reference guides, will be developed, published, and posted on an online resource center that is accessible to the public. This center will provide stakeholders with the latest information about drug addiction genetic science and related law and policy.

“We hope that our findings have some influence on the development of state laws and policies for the use of this genetic data in these settings. Right now there’s no uniformity. Jurisdictions may treat this information very differently,” he said.

Other sites involved in this research include the Mayo Clinic Foundation, Rochester, Minn.; Stanford University, Palo Alto, Calif.; University of Louisville, Louisville, Ky.; St. Louis University, St. Louis, Mo.; Hastings Center, Garrison, N.Y.; and the Pacific Institute for Research and Evaluation, Louisville, Ky.

Dr. Rajagopalan received a $1.718 million five-year renewal grant from NIH to continue her study of how tuberculosis bacteria multiply and spread inside the body. The original NIH grant funding her research was awarded in 2000.

During the years of the first grant, Dr. Rajagopalan and her team identified and described several proteins that TB bacteria need to divide and reproduce.

“Some exciting work last year led us to believe that TB bacteria in lab cultures divide differently than they do inside the body’s host cells. The purpose of this grant is to examine how the TB bacteria grow inside tissues. What allows tuberculosis to stay dormant for many years in the body?” she said.

“We’re looking at more proteins that we think are involved in cell division. One of these proteins, FtsZ, is a potential drug target. If we know how it behaves inside the cell, we can develop drugs that interfere with it,” she said.

To understand how FtsZ operates, Dr. Rajagopalan and her team are tracking down other proteins that regulate it.

“We don’t yet know what they are. We’ve identified one, and there are about 10 other candidates that we’re looking at,” she said.

The bottom line is to figure out what regulates the division of TB bacteria. What happens to TB bacteria during their dormant phase? Are there proteins that shut down cell division? These are the questions Dr. Rajagopalan wants to answer.

Dr. Pendurthi received a $962,000 four-year grant renewal from the NIH to continue her investigation into how the blood-clotting process affects the biology of the cell, as well as how it affects the growth of cancerous tumors. She received the initial grant in 2000.

“In the first grant, we identified a number of genes that are activated in lung and vascular cells as a response to factor VIIa binding to tissue factor – the process that triggers blood clotting,” Dr. Pendurthi said.

“In this grant, we will study the role of tissue factor in tumor growth and the spread of cancer to distant organs. We believe the results of this study will help identify new drug targets for metastatic breast cancer,” she said.

“Most large and aggressive tumors produce a lot of tissue factor, which is displayed on the outside of the cancer cells. Sometimes little pieces of the cancer cells shed off the tumors into the bloodstream and cause fatal blood clots,” Dr. Pendurthi said.

The blood-clotting process works like this: tissue factor is fixed to cells that are present outside blood vessels, while factor VIIa is freely circulating with the blood inside the vessels.

When these vessels are damaged, blood comes in contact with cells containing tissue factor. Factor VIIa activates the coagulation cascade that makes blood clot, but scientists still don’t understand the mechanism of healing, she said.

“We found that factor VIIa, with the help of tissue factor, can trigger the production of several proteins. We are the first to show the production of some of these proteins. Now we have to investigate their role in healing and other disease processes,” Dr. Pendurthi said.

These newly made proteins tell the cell what to do next, whether to grow, divide, or move away and settle in other places in the body.

In the initial grant, Dr. Pendurthi and her team studied how certain proteins regulated these genes. In this grant, they are taking a more global view, trying to understand how these genes work with other genes in cancer biology and how they affect wound healing.

Dr. Rao received a two-year renewal grant for $309,776 from Novo Nordisk to fund his investigation into improving the effectiveness of NovoSeven, a drug used to prevent bleeding in people with hemophilia, an inherited genetic illness that impairs the body’s ability to control bleeding.

This is the fifth grant Dr. Rao has received from Novo Nordisk, a pharmaceutical firm headquartered in Denmark. The firm has awarded him more than $1 million in the past 10 years to support his research.

NovoSeven, commonly known as recombinant coagulation factor VIIa, has proven to be safe and effective in the treatment of bleeding in people with hemophilia. It has been approved by the U.S. Food and Drug Administration.

“Further, preventively treating hemophilia patients with factor VIIa has been shown to reduce the frequency of their bleeding episodes and prevent joint damage, thus significantly improving their quality of life,” Dr. Rao said.

This drug also shows promise for treating people with excessive or life-threatening bleeding, such as patients undergoing major surgery or wounded soldiers in the battlefield, he said.

“Unfortunately, the drug disappears very quickly from the body, so it has to be given repeatedly. This makes treatment very expensive, as well as making it impractical to self-administer the drug,” Dr. Rao said. Novo Nordisk is currently developing a new generation of drugs designed to overcome this limitation.

“Our current research focuses on characterizing these newer drugs in the laboratory using cells isolated from blood and the blood vessel wall. The results of our study will help determine if these new drugs can be used in clinical medicine to treat bleeding episodes,” he said.

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