2007 Innovative Development Awards Recipients

Kyung-Seon Lee
Assistant Project Scientist
MED: Pathology
Summary of Research: The chemotherapeutic agents in the current market have developed multi-drug resistance and there is a call for new anticancer drugs with novel structures and functions. For discovery of anticancer agents, plants and marine organisms have served as major sources, but have drawbacks with sustainability concerns, time-consuming isolation processes and low concentrations of relevant compounds. An alternative to discovery anticancer agents is combinatory chemistry. However, combinatory chemistry itself has its own limitations and requires natural products as motifs in new drug discovery. Another living organism that has a high potential to be a novel source in new drug discovery is endophytes. Endophytes are defined as organisms such as bacteria and fungi that reside within a plant symptomlessly colonizing in the internal tissues in mutualistic or symbiotic association with the host. Fungal endophytes, in particular, appear promising as a source of novel drug discovery due to: 1) host specificity, 2) production of diverse secondary metabolites with under explored biodiversity, 3) production of clinically important phytochemicals of the host, and 4) ease of large scale culturing by morphological engineering to improve growth rates and production of secondary metabolites. The goal of this pilot project is to isolate fungal endophytes from anticancer plants dispersed in Solano and Yolo Counties, Northern California appearing in ethnobotanical history of anticancer therapies established by indigenous American Indians. Fungal endophytes will be isolated from surface-sterilized plants with 70% ethanol and 5% sodium hypochlorite. Cytotoxicity will be tested in vitro in human cancer cells, including liver and breast cancer cell lines. If fungal endophytes that produce cytotoxic compounds are discovered from this pilot work, future studies will focus on bioassay-guided isolation and determination of structures using chromatographic separation and spectroscopic analysis, and identification of direct target(s) of the cytotoxic compound(s) to understand mechanisms of action.

Elizabeth Mitcham
Pomologist and Specialist
Plant Sciences
Summary of Research: Pome fruits, such as apple and pear, have not been studied extensively at the genetic level. Despite the nutritional importance of pome fruits to the North American diet, the large production acreage, and fresh market sales in excess of 2 billion dollars annually, the development of genetically transformed fruit trees remains unfeasible due to time, cost and legislative hurdles. Therefore, scientists studying physiological aspects of pome fruit at the gene expression level are forced to infer what might happen in apple and pear based on what does happen in tomato. Unfortunately, pome fruits produce an entirely different class of pigments, aromatic volatiles, flavor compounds, as well as countless other proteins that are involved in making a pome fruit look, smell and taste like a pome fruit. Utilizing virus-induced gene silencing (VIGS) technology offers a potentially elegant and relatively rapid means (as opposed to genetic transformations) of evaluating gene expression in pome fruit by inhibiting the expression of a single gene from a pathway of choice, without influencing the expression and activity of other unrelated pathways. This technique offers a powerful new tool for studying gene expression previously unavailable for pome fruit physiologists. Indeed, the potential application of this technology would eventually be extended to all postharvest fruit and vegetables, enabling scientists to study any pre- or post-harvest cellular phenomena of interest. The knowledge gained from these experiments would subsequently be used to develop novel compounds, make alterations in storage and handling recommendations for apple fruit, and as a breeding tool to develop pathogen and physiological disorder-resistant or high color or high nutritional content strains of fruit. More importantly, the adaptation of VIGS technology will open the door for evaluation of gene expression in pome and other postharvest fruits and vegetables, thereby stimulating countless research studies and numerous collaborative efforts by postharvest physiologists the world over, and enabling access to the full spectrum of funding sources, from federal granting agencies through to commodity groups and marketing boards.

Senthil Venugopal
Assistant Adjunct Professor
MED: Internal Medicine
Summary of Research: Hepatocytes appear to respond to injury along a continuum. When the insult is mild, the cells predominately undergo regeneration with lesser degrees of cell death; whereas, when the insult is severe, they mostly undergo apoptosis with less ability to regenerate. The fundamental difference in the cell response depends on the extent of the injury process. From the available data, it appears that there might be tight genetic regulators that decide the cell fate. Recently, microRNAs (miRNAs) have emerged as novel genetic regulators that control cell functions at a post-transcriptional level in various organisms from plants to humans. They bind to the corresponding mRNAs and degrade them, thus modulating gene expression. Hence, we hypothesize that one mechanism by which the injury process modulates hepatocyte function is by altering the expression of miRNAs. Our preliminary microRNA micorarray data using an in vivo liver injury model system showed that there was a differential expression of microRNAs between mild injury and severe injury. For example, overexpression of miR-491, one of the miRNAs found to be unregulated in severe injury in vivo, caused Hep G2 cells (human hepatoma cell line) to undergo TNF-induced apoptosis. Our intent is to determine the functional role of miRNAs in modulating hepatocyte functions during liver injury. Specific Aim #1: To study the functional role of microRNAs in hepatic cells. Hep G2 cells will be transfected with either miRNA precursors or miRNA inhibitors. These transfected cells will be analyzed for apoptosis and proliferation assays. Specific Aim #2: To study the protein targets of miRNAs in hepatic cells. The predicted protein targets of these miRNA will be identified using Sanger and MIRANDA miRNA target prediction softwares. The target proteins that are involved in either cell proliferation or apoptosis will be evaluated by Western blots an/or activity assays. The results from these studies will provide novel pathways for the regulation of liver cell functions.

Martin Wu
Associate Project Scientist
UC Davis Genome Center
Summary of Research: Formation of mitochondria, the ATP-generating organelles of eukaryotes, is one of the seminal events in the evolution of eukaryotic cells. Overwhelming evidence supports the endosymbiosis theory that mitochondria originated once from within a specific group of bacteria called a-proteobacteria, probably 2 billion years ago. Inference of ancient evolutionary history such as origin of mitochondria is difficult and requires a large amount of molecular sequence data. Although the steady stream of genome (a genome is all of a living thing’s genetic material) sequences of both a-proteobacteria and mitochondria has very much expanded our view of this event, the exact phylogenetic (evolutionary) position of the ancestor of mitochondria within the a-proteobacteria remains unresolved, partly due to the phylogenetically sparse and uneven sampling of the a-proteobacterial genomes. Here I propose to sample a richer taxonomic group of 5 a-proteobacteria by sequencing 32 universal genes present in their genomes. Genome-level phylogenetic analyses using this multi-gene dataset would allow me to pinpoint the origin of mitochondria more precisely and confidently. Preliminary results from this study will be used as the basis for a proposal to National Science Foundation’s year 2008 Assembling the Tree of Life program.

Zongbing You
Assistant Adjunct Professor
MED: Orthopaedic Surgery
Summary of Research: Articular cartilage damage due to injuries or arthritis is a critical medical problem. No optimal treatment has been developed, because the origin, development and mature features of articular chondrocytes have not been understood. We have discovered doublecortin (DCX) as a marker for articular chondrocytes. DCX was originally found in neurons and was involved in neuron migration. Therefore, we have formulated a general hypothesis that DCX is a lineage-specific marker for articular chondrocytes and DCX may play an important role in articular chondrocytes. Our long-term goals are to understand how mesenchymal stem cells differentiate into articular chondrocytes and the mechamisms by which articular joint is formed. Our specific aims are: (1) to determine if DCX is a lineage-specific marker for articular chondrocytes; (2) to determine the function of DCX in artiuclar chondrocytes; and (3) to determine if DCX plays any role in the joint diseases. The accrued knowledge will significantly advance our understanding of joint development and may potentially provide new strategies for treatment of articular cartilage damage due to injuries or arthritis.

Hu Zhan
Assistant Project Scientist
Summary of Research: Probing the Cosmic Structure and Constraining Dark Energy with Millions of Supernovae: We propose to measure the large-scale structure of the universe with millions of type Ia supernovae (SNe) and to constrain dark energy using both the angular correlation and luminosity distances of the SNe. Dark energy is a major but poorly understood component of the universe that drives the accelerated cosmic expansion. SN luminosity distances have shown the first decisive evidence of dark energy, but the conventional SN technique will not be so powerful as emerging techniques that utilize the statistics of the galaxy distribution and/or those of the underlying cosmics density field. Since SNe explode in galaxies, they can, in principle, be used as a tracer of the large-scale structure like their host galaxies. Furthermore, SNe, being point sources and brighter than their hosts, can be observed at a greater distance regardless the host luminosity or type and thus can form a more complete sample. Unfortunately, one cannot use SNe to probe the cosmic structure with current surveys because of the small sample size, but ambitious dark energy surveys in the near future will obtain SNe photometrically in the millions over a large fraction of the sky. It is imperative to make a timely assessment of the dark energy constraints from both the angular correlation and luminosity distances of type Ia SNe. The results will be useful in the planning of future surveys.