Current Research
Dr. Mei-Zhen Cui’s laboratory is focused on the molecular and cellular mechanisms of heart disease. Her laboratory integrates molecular, cellular, and genetic approaches to discover the mechanisms that control the progression of artery wall disease, which leads to heart disease and stroke. The research group was the first to reveal the possible link of oxidized low-density lipoprotein (oxLDL) and lysophospholipids to thrombosis (formation of a blood clot inside a blood vessel). Their research provided evidence that oxLDL and one type of lysophospholipids- lysophosphatidic acid (LPA) induce the expression of tissue factor, a blood clotting initiator. LPA is an active component of oxLDL. The research further uncovered LPA's influence on vascular disease with evidence that LPA induces expression of early growth response protein 1, Egr1, a key transcription factor that mediates a broad spectrum of vascular pathologies. The research team has recently discovered that the matricellular protein Cyr61 (CCN1) is the key mediator for LPA-induced artery wall smooth muscle cell migration. The arterial smooth muscle cell migration from the tunica media to the intima represents one of the initial steps in development of arterial wall disease. Their work provided a new concept that the matricellular protein Cyr61 bridges the LPA signaling pathway with the integrin pathway, leading to arterial wall smooth muscle cell migration. These new discoveries, including the newly identified intracellular pathways and the related regulatory molecules, may serve as therapeutic targets for the prevention and treatment of heart disease and stroke.
The recently funded studies by the National Institute of Health are based on these previous novel findings and new observations. The central goal of the proposal is to reveal the pathological role of lysolipid LPA in the development of atherosclerosis, a type of hardening of the arteries. Cardiovascular disease is the number one cause of death and disability in the United States. Understanding the basic mechanisms of atherosclerosis paves the way for new prevention and treatment approaches.
Dr. Xu’s research laboratory focuses on the study of neurodegenerative diseases, especially Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). AD and ALS are both devastating neurodegenerative diseases for which there is currently no cure. AD and ALS are characterized by degeneration of select populations of neurons in certain regions of the brain and spinal cord, as well as the association of misfolded proteins that renders them neurotoxic and prone to aggregation.
The overall goal of our research is to understand the molecular mechanisms underlying AD, ALS, and related neurodegenerative diseases and identify novel therapeutic targets for the development of treatments and prevention of these diseases. In the course of our study, we have recently identified a novel molecule that plays a crucial role in the pathogenesis of ALS. Using our newly created mouse model, our current data demonstrated that inactivation of this particular gene greatly improved motor function and extended the lifespan of ALS model mice. Further development of this promising new line of research may lead the identification of new therapeutic targets for the development of prevention and treatment of this devastating disease.
Dr. Nin Dingra’s Research Lab is testing the therapeutic properties of carbon monoxide. Although carbon monoxide (CO) is well known as a poison, humans endogenously produce CO in a biochemical process mediated by a class of enzymes called heme oxygenases (HO). The process involves conversion of heme to ferrous iron, CO and biliverdin. CO has recently been reported to be an important signaling molecule in the body and categorized as a member of gas transmitters along with nitric oxide (NO) and dihydrogen sulfide (H2S). CO shares similar pathways with the other gas transmitters to exert its cytoprotective effect. Several roles of endogenous CO in physiological functions have been uncovered. The first evidence of vasorelaxation by CO was reported about three decades ago showing that exogenous CO can cause the relaxation of rat coronary artery. The cardiac defense mechanism of heme oxygenase-1 and endogenous CO by vascular tone relaxation was proven later. Several findings suggest that actions of heme oxygenase-1 lead to protective effect in atherosclerotic diseases. CO is also known to be involved in body’s defense system by modulating the production of proinflammatory cytokines, cell proliferation and apoptosis. In addition, other studies have shown the importance of CO in the conditions such as inflammation, vasodilation, muscle dystrophy, tumor cells, and the neuroendocrine system. A few studies have also shown antimicrobial effect of CO against diverse microorganisms, including Gram-positive and Gram-negative bacteria. Currently, many studies are being conducted to draw a more detailed picture of the therapeutic power of this gas molecule.
Our research goal involves designing pharmaceutical compounds capable of releasing CO in a tunable rate and has low toxicity towards biological systems. We have recently shown that amine carboxyboranes are a group of molecules that can be used as carbon monoxide releasers. Our findings indicate amine carboxyboranes to be very slow CO releasers at physiological pH and temperature. We have also found that spontaneous CO re-lease process under normal physiological condition can be accelerated with reactive oxygen species (ROS). Ultimately, in vivo studies for the pharmacokinetics of these compounds using animal models are expected. Before that stage, in order to predict if these compounds are pharmacologically significant, many in vitro studies using cell cultures need to be completed. Our plan includes gathering the basic understanding of amine-carboxyboranes as the CO releaser and to see compatibility in the biological systems. Cytotoxicity will also be determined to get a more thorough analysis of how tolerant the cells are towards these molecules. With advancing technology, many metabolic profiles ranging from metabolic stability to toxicology can now be delivered by relevant human in vitro models. These experiments all together will provide a better understanding of these compounds as CO releasing molecules and uncover their potential as a pharmaceutical drug.
In addition to the above goal, we also plan to use amine-carboxyborane molecules as a CO provider and determine the effects of CO at a cellular level. One of the areas we are interested is to test the effect of carbon monoxide on the redox state of the cells. We are using genetically engineered yellow fluorescence protein (YFP) as a tool to test redox states. This protein responds to the redox states and exist in the oxidized and reduced forms which are detectable by different methods. Using the signal intensity observed, we can quantify the reduction potential in the cellular environment. We will determine whole cell redox states as well as subcellular level states of whether they show oxidizing or reducing conditions. For instance, YFP can be engineered to localize into the mitochondria or a nucleus and we can detect their response to the redox states in these compartments. This study can reveal more information on how CO exerts its effects. More studies are expected to fully understand the detailed mechanism of this mysterious CO molecule and we hope to accomplish some of them.
In summary, a breakthrough for CO therapy requires concurrent investigations of the precise role of CO and its targets within the organisms as well as preparation of pharmaceutical compounds that can safely deliver CO. The outcome of our research will provide evidence one-step closer to approach that goal.
Dr. Ayudhya’s Research Lab aims at preparing drug-conjugated carboxyboranes that can release CO and potentially be used as a drug delivery system. Carboxyborane moiety is used to deactivate drug molecules and to target and release them at the site where they are needed which therefore will reduce unnecessary side effects. We have used drugs such as (Namenda: an Alzheimer’s drug) and tamoxifen (Nolvadex: a breast cancer drug), on the carboxyborane moiety to prove this concept. We are working towards selective drug delivery to the disease sites.
Dr. Dong’s research lab focuses on the design and synthesis of xanthine oxidase inhibitors for treatment of Gout disease. Approximately 8 million people in America are affected by gout. The Gout cases have risen over the past two decades. The xanthine oxidase inhibitors (XOI) are small molecule drugs recommended in reducing the urate level to prevent gout attacks in adult patients. The current drugs either exhibit side effects or are very expensive. Cost-effective xanthine oxidase inhibitor design and synthesis are an important outcome from this research.
The first and second generation of medicines available in North America, Asia, and Europe, are allopurinol and febuxostat respectively. The latter’s price is $130/month with less side effect compared with $10/month of the former. While the third generation, FYX051(topiroxostat) is available in the Japanese medicine market and costs $150/month. It is desirable to design and synthesize inhibitors with less side-effect, less cost and higher efficacy.
Dr. Dong’ research group aims to synthesize FYX051 analogs for investigation of the effect on half life of xanthine oxidase inhibitor and evaluate their cost-efficacy with enzymatic kinetics studies. These results are expected to yield potential gout-treatment candidates.
Dr. John Garza’s Research Lab
Specialization in Predictive and Descriptive Analytics
- Permutation and Non Parametric Multivariate Analysis
- Principle Coordinates Analysis
- Principle Components Analysis
- Linear Discriminant Analysis
- Correlation Analysis
- Logistics Regression