New NIH funding awarded to the Department of Bioengineering and Therapeutic Sciences in 2011

New research support awarded to the UCSF School of Pharmacy by the National Institutes of Health during the 2011 fiscal year included a half-dozen on-going projects by BTS faculty:

Genetic mutations and liver cancer

Xin Chen, PhD

• Associate adjunct professor
• Awarded two new grants totaling $351,488 from the National Institute of Alcohol Abuse and Alcoholism (part of a two-year $405,563 grant) and the National Cancer Institute (part of a two-year $369,642 grant)

Elisabeth Fall

Xin Chen, PhD

In the first of the two new studies, Chen focuses on how alcohol contributes to liver cancer development. Increased alcohol consumption leads to liver diseases and eventually liver cancer. In this study, Chen is investigating genetic mutations that contribute to alcohol-induced liver cancer development in mice.

In the second new study, Chen is focusing just on hepatitis B (HBV) and hepatitis C (HBV) infections, the major risk factors for liver cancer. While it is known that HBV and HBV play direct roles, the resulting cancer takes a long time to develop and often does not occur at all. She seeks to determine what additional or on-going genetic mutations are occurring in the virally damaged liver cells.

Chen aims to precisely determine which changes to key liver cell genes lead to cancer, providing the basis for better ways to prevent and treat the disease.

New devices to treat retinal diseases

Tejal Desai, PhD

• Professor and vice chair for education
• Awarded $379,264 from the National Eye Institute as part of a four-year $1.5 million research grant

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Tejal Desai, PhD

Desai is developing a nanoporous thin-film device that can be used to treat eye disease. It will be as thin as a strand of hair with pores about 25 nanometers in diameter. Once deployed into the back of the eye, the device will deliver sustained doses of medications that can effectively fight the wet form of macular degeneration, a disease that damages sharp, central vision.

The new drug diffusion device would have multiple advantages over current treatments, which call for monthly injections of drugs into the eyeball with large-bore needles. Beyond the daunting discomfort, the injection method is neither pharmacologically optimal nor cost efficient due to the drugs’ rapid breakdown and clearance from the body.

By contrast, the new device would protect the drugs from degradation and deliver a sustained dose over several months. This study will develop and test prototypes in in vitro and animal eye models.

Desai’s research seeks to create new and improved tools for treating retinal diseases.

Biosensors that detect and respond to small molecules inside cells

Tanja Kortemme, PhD

• Associate professor
• Awarded $231,750 from the National Institute of Biomedical Imaging and Bioengineering as part of a two-year $424,875 research grant

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Tanja Kortemme, PhD

Kortemme seeks to create a new type of modular sensor made from biological materials; in this case, protein molecules inside cells. Such sensors would allow real-time detection of small molecules such as intracellular signals, metabolites, and drugs inside living cells and organisms.

The biosensors will be made by reengineering heterodimeric proteins, which are pairs of proteins that normally interact to fulfill their biological roles. For the sensors, they will be altered so that they can only come together when a particular small molecule is present. This will be done by transplanting binding sites for the small molecules into the protein-protein interface.

The reengineered proteins will also each be linked to half of a so-called reporter, such as green fluorescent protein, that has been split in two. The reporter will only glow when the reengineered proteins combine, thus signaling the presence of the small molecules.

That split reporter can also be an enzyme, which is a protein molecule that affects the rates of chemical reactions and thus controls biological processes. In that case, when the heterodimeric proteins combine in the presence of the small molecules, the enzyme will be rejoined and activated.

Thus, Kortemme’s biosensors may go beyond detecting small molecules. If the reporter proteins she uses are enzymes, the biosensors could also control biological processes, such as activating cellular events that make more of the target molecules or metabolize them if, for example, they are toxic.

Kortemme is making new tools to detect and respond to many molecular targets. The biosensors could be used for probing cellular processes or for new medical diagnostics and treatments.

Inducing antibodies to neutralize HIV

Francis Szoka, PhD

• Professor
• Awarded $193,125 from the National Institute of Allergy and Infectious Diseases as part of a two-year $424,875 research grant

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Francis Szoka, PhD

Szoka is making molecules known as immunogens designed to stimulate a virus-neutralizing immune system response against a region of an HIV protein called GP41.

GP41 is part of a protein complex embedded in and protruding from HIV’s viral envelope. The complex allows the virus to attach to and enter T-cells via a surface receptor called CD4.

The region of GP41 that Szoka is focusing on is the target of ongoing HIV vaccine development aimed at triggering the response of antibodies that would neutralize the virus before it enters cells.

Szoka’s unique approach is to stimulate that immune response with immunogens (linked amino acids called peptides) that mimic the targeted GP41 region but include specific chemical alterations (post-translational modifications) that may occur in that part of the protein during HIV infection.

Szoka hypothesizes that it is those modifications that induce the neutralizing antibodies to recognize the GP41 region.

His lab has synthesized chemically modified peptides that mimic the protein region and incorporated the immunogens into lipid nanocapsules. He thinks this will maximize the immune response and generate neutralizing antibodies to HIV.

Szoka will ultimately use the most effective immunogens in a vaccine meant to induce HIV-neutralizing antibodies, which could be a precursor to a vaccine to prevent AIDS.

Modeling and probing the cell cycle

Chao Tang, PhD

• Adjunct professor
• Awarded $410,793 from the National Institute of General Medical Sciences, part of a four-year $1.6 million research grant

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Chao Tang, PhD

Tang is developing mathematical models of how cell division and replication (cell cycle) are regulated. The cell cycle is one of the most fundamental and complex biological processes, and one that goes awry in cancer’s cellular proliferation.

In this project, Tang is building and validating computer models of the entire cell cycle system in yeast, which share similar cell cycle processes and proteins with human cells. He is focusing on key checkpoints and switches that ensure the process, including the accurate and complete replication of DNA, is occurring correctly.

Tang plans to use his computer models to identify the effects of different disturbances on the entire cell cycle regulation system and at key checkpoints. He will use experiments in actual yeast cells to test his mathematical model’s predictions.

Tang expects that simulating disturbances of the cell division process will help explain why certain gene mutations can lead to cancer and may suggest new treatments.