Research that aims for historic discovery

By Deborah Wormser

(L-R) Drs. Meg Phillips, Lani Wu, and Steven Altschuler 

Five faculty members have received new grants from the High Risk/High Impact Program at UT Southwestern Medical Center for research to help explain the actions of anti-malarial drugs and studies to advance the treatment of diseases linked to RNA-splicing errors, diseases such as cancer and Duchene muscular dystrophy.

The program provides a year of funding to test a hypothesis that holds a substantial risk of failure but has the potential to greatly influence the science or practice of medicine, if supported by the research.

In one research project, Dr. Meg Phillips, Professor of Pharmacology, and Dr. Steven Altschuler and Dr. Lani Wu, Associate Professors in the Cecil H. and Ida Green Center for Systems Biology and in Pharmacology, will study how drugs act on the parasite that causes malaria.

In nominating them, Dr. David Mangelsdorf, Chair of Pharmacology, and Dr. Rama Ranganathan, Director of the Green Center for Systems Biology, noted that the Altschuler and Wu labs possess a unique ability to conduct rapid and image-based high-throughput screening using software they jointly developed, while Dr. Phillips has unparalleled expertise in anti-malarial drug development.

High-throughput screening involves searching through thousands of compounds to identify those with the most promise. The researchers will screen for compounds to treat malaria, a mosquito-borne disease that annually afflicts an estimated 220 million people and causes 700,000 deaths. They plan to determine the effects of these potential anti-malarial compounds both on the pathogen and on the host’s red blood cells, with an emphasis on the signaling pathways within the cell that are affected by the compounds.

“Because of the issues of rapid drug resistance, all new anti-malarial agents are partnered with another agent before reaching clinical use. By obtaining insight into which compounds act on similar pathways, our studies will help determine drug partner combination strategies,” the researchers wrote in their grant proposal.

They explained that knowing how a compound acts and how quickly it kills the pathogen should enable prioritization of publicly available compounds, which in turn will help chemists determine which compounds to develop.

Drs. Balajee Somalinga (left) and Philip Thomas

For the second project, Dr. Philip Thomas, Professor of Physiology, and Dr. Balajee Somalinga, Instructor of Physiology, will work to develop a novel, easy-to-use, genetically encoded RNA splice sensor.

RNA splicing is an important step that occurs in the nuclei of cells as RNA matures and is required for its many functions, including coding for correct protein sequences. Although splicing errors cause many diseases, studying those errors and discovering new disease treatments have proved challenging because of difficulties in assessing RNA splicing, particularly in living cells.

If effectively developed, the new study method would overcome the obstacles of the current methods of analyzing RNA splicing and may enable discovery of new therapies for splicing disorders.

 “If successful, the proposed assay will have an immediate and high impact on basic research and, eventually, on clinical research. It will enable the development of new approaches that may alter the course of intractable diseases,” said Dr. James Stull, Chairman of Physiology.

A total of 43 faculty members have received grants through the High Risk/High Impact Program, which was established in 2001.

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Dr. Altschuler is a W.W. Caruth, Jr. Scholar in Biomedical Research.

Dr. Mangelsdorf holds the Distinguished Chair in Pharmacology, and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.

Dr. Phillips holds the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science, and the Carolyn R. Bacon Professorship in Medical Science and Education.

Dr. Ranganathan holds the Cecil H. and Ida M. Green Chair in Biomedical Science.

Dr. Stull holds the Fouad A. and Val Imm Bashour Distinguished Chair in Physiology.

Dr. Thomas holds the Ruth S. Harrell Professorship in Medical Research.

Dr. Wu is a Cecil H. and Ida Green Scholar in Biomedical Computational Science.

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