DISEASE-RELATED RESEARCH AT HWI

HWI scientists work diligently to contribute to the body of knowledge that underlies medical practice. The impact of their basic research studies is far reaching. The development of new therapies and cures for devastating diseases often depends on the kind of molecular-level information that is the product of the structural biology research conducted at HWI and similar institutions. Typically, this research involves the study of protein molecules, especially the type of proteins that function as biological catalysts and are known as enzymes. The following paragraphs give a brief description of the variety of disease-related studies currently underway at HWI.

AIDS

• A major concern of immunocompromised patients, in particular those with AIDS, is susceptibility to infection caused by opportunistic pathogens. Pneumonia caused by fungi of the genus Pneumocystis is one of the most frequent and severe of these opportunistic infections. A major focus of Dr. Vivian Cody's laboratory is to characterize the structural and biochemical properties of a Pneumocystis-specific enzyme in order to design effective inhibitors that have potential as therapeutic agents for the treatment of AIDS-related pneumonia.

ARTHRITIS

• HWI scientist Michael Malkowski is working to provide insight into how non-steroidal anti-inflammatory drugs (NSAIDs) affect the inflammatory process. Dr Malkowski's studies may lead to the development of new medications for treating rheumatoid arthritis, osteoarthritis, and other inflammatory disease with fewer side effects.

BREAST CANCER

• Many breast cancers are dependent on estrogen (the female sex hormone). The Ghosh lab is examining three enzymes that play a critical role in controlling the level of estrogen present in breast tissue. These enzymes will serve as vital targets for the design of new drugs that will inhibit the growth of hormone-dependent breast tumors.

CANCER (general studies)

• Hormone receptors and molecular chaperones are cancer-related molecules under study in the Gewirth laboratory.  The receptors include the androgen (male hormone) receptor, which is an important cellular mediator of prostate cancer, as well as the vitamin D receptor, which may play a role in the prevention of colon cancer. Dr. Gewirth is also examining proteins in the hsp90 family of molecular chaperones. These proteins are required for the maturation of other protein molecules including those that initiate or maintain cancer.  Inhibitors of hsp90s are potent anti-tumor compounds, and Dr. Gewirth's lab is working to develop new classes of these inhibitors.
  
  
• Dr. Vivian Cody is working with scientists at the University of Minnesota to design novel cancer drug-delivery systems. These systems are being tested with drugs that bind to the enzyme dihydrofolate reductase (DHFR), an important target for chemotherapy. Dr. Cody is carrying out crystallographic studies of DHFR-drug complexes in order to verify that the potential drug-delivery systems are functioning as intended.
   
• The Umland laboratory is studying how the interactions between DNA and a class of proteins known as "Hox" proteins regulate normal stem-cell proliferation and differentiation in adults. Malfunction of the Hox proteins is the cause of several different cancers including leukemia.

CYSTIC FIBROSIS

• The bronchial tubes of cystic fibrosis patients contain thick mucus that clogs the lungs and leads to chronic bacterial infections.The bacteria responsible for these infections require iron in order to grow. They secrete compounds known as siderophores that solubilize iron found in their surroundings and make it available for uptake. Dr. Andrew Gulick is studying several enzymes essential for siderophore production. His goal is to discover how to inhibit these enzymes, thereby preventing bacterial growth.

DIABETES

• Vascular disease is an important complication of diabetes. The laboratory of Dr. Edward Snell is working on two proteins, extracellular superoxide dismutase and fibulin-5, which have been reported to play a role in preventing the oxidative damage to blood vessel walls that occurs in diabetes. Dr. Snell hopes to learn how the two proteins bind together and how binding is altered in diabetic patients.

DISEASES LINKED TO A FAMILY OF ENZYMES

• Dr. William Duax is predicting the biological properties of enzymes belonging to the short-chain oxidoreductase family and testing those predictions using x-ray crystallography. Members of this family are linked to many diseases including cancer, hypertension, tuberculosis, Alzheimer's disease, infertility, ulcers, and polycystic kidney disease.

EMERGING INFECTIOUS DISEASES (SARS)

• Within months of the appearance of Severe Acute Respiratory Syndrome (SARS) in 2003, HWI scientists Wayne Schultz and Tim Umland initiated collaboration with ZeptoMetrix, a Buffalo-based biotechnology company, and Virionyx, a biopharmaceutical company headquartered in New Zealand. The roles of Drs. Schultz and Umland on this project are two-fold. They are supplying their collaborators with purified proteins for use in creating a passive vaccine, and they are identifying virus•host protein complexes important for the adaptation of the virus to a new host. They hope also to apply this research strategy to other emerging diseases such as West Nile Virus and Dengue Fever.

MACULAR DEGENERATION

• Macular degeneration leads to progressive loss of vision and is often the result of genetic disease.  In collaboration with scientists at the University at Buffalo, Dr. Debashis Ghosh is working to determine the structure and function of interphotoreceptor retinoid-binding protein (IRBP), a protein involved in degeneration of the retina. By determining the structure of this molecule, the Buffalo scientists may be able to find ways to treat and prevent some cases of macular degeneration.

MELANOMA

• Dr. Debashis Ghosh is working with colleagues at Roswell Park Cancer Institute to design rationally peptides that would have specific interactions with antibody molecules and hence would trigger optimal immune response against the tumor-associated antigens of melanoma cells. This project could lead to optimally active immunogenic peptides against melanoma.

POLYCYSTIC KIDNEY DISEASE (PKD)

• Dr. William Duax and members of his research team are working to determine the structure of one of the largest proteins in the human body, polycystin 1. Mutations in this protein are responsible for hereditary PKD, which affects one in 1,000 people. Their results will help us to understand how mutations cause this disease and may lead to the design of new medications for treating PKD.

THYROID-RELATED STUDIES

• Integrins are proteins involved in communication between cells that can control the life and death of tumor cells.  Recently, integrins have been identified as cell-surface receptors for thyroid hormones, opening up new opportunities to design thyroid hormone-based agents that should not impact normal thyroid function.  In collaboration with the Davis group at the Ordway Research Institute (Albany, NY), Dr. Cody is studying the molecular interactions between thyroid hormone and integrin.
  

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