Research
Research Summary
Our research focuses on three major topics: chronic disease early detection, chronic disease prevention, and chronic disease treatment. We currently are using cancer as the model of chronic diseases to establish the principles and to demonstrate their feasibility.
Chronic Disease Early DetectionNearly one in two Americans has a chronic medical condition of one kind or another. Chronic diseases have drastically deteriorated the quality of life and have imposed a tremendous economic burden among the general US population with a few examples as shown in Table 1.
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Table 1. Annual deaths and economic burdens of the top three chronic diseases in the U S.
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(Year 2005)
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Heart disease
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Cancer
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Chronic lower respiratory disease
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Disease-induced Death (X103)
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652
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559
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130
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Economic burden (billion $)
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448
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219
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43
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The major barriers that impede the improvement of the control of these diseases are 1) the lack of information about the initial molecular changes that lead to these diseases and 2) the lack of feasible early detection of these diseases. Such a status is mainly because of the current scientific and clinic paradigm in use to fight against these chronic diseases – we envision that studying the cause of chronic disease have been focusing on those changes that accompany or occur after pathological progression, which have been used as the guidance for early detection and clinical intervention. Such molecular changes, due to the latent nature of chronic diseases, very likely are not the original changes leading to these chronic diseases. We are working to establish a new paradigm for the control of chronic diseases by determining the original/initial molecular changes that are involved in the initiation of chronic diseases. This approach will open up new opportunities to significantly improve our success in fighting chronic diseases.
Specifically, in collaboration with Professor Jian-Ping Wang and his colleagues from the Department of Electrical and Computer Engineering, the pioneers in nanotechnology, we are developing a GMR sensor- and high magnetic moment nanoparticle-based detecting platform that can detect and quantify proteins in body fluid with high sensitivity, specificity and feasibility. Such a platform allows longitudinal monitoring of biological molecular changes, establishing the foundation for early-stage chronic disease biomarker identification and validation, and early chronic disease detection. In collaboration with Professor Fekadu Kassie from the Department of Veterinary Medicine, Professor Joel Slaton from the Department of Urology, and Dr. Paul Limburg and Professor Daniel Gallaher, we are exploring the applicability of diagnosing early-stage lung cancer, prostate cancer, and colorectal cancer in clinical setting.
Representative publications:
Cancer Chemoprevention Cancer is a deadly disease that leads to hundreds of thousands of death in U.S.A. annually. Chemoprevention is one potential strategy that will help control the development of various malignancies. Compared to cancer chemotherapies, there are very few effective chemopreventive agents in clinic use, urging the need to search for new potential chemopreventive candidates. The ultimate goal of this research is to develop safe and chemopreventive agents that can be used to slow, delay, or prevent the development of the deadly malignancies. One strategy is to search for chemopreventive candidates from natural food and beverages, which may lead to single-component identity or a mixture-based CAM modality. The other approach is to develop synthetic candidates based on the lead nature provides.
Kava Piper methysticum is a historically long-standing crop in South Pacific islands and kava is the extract of the roots of Piper methysticum. Traditional kava has been consumed for centuries in South Pacific islands. The negative correlation between the amount of kava consumed and cancer incidence among the nations in South Pacific suggests that kava is potentially chemopreventive. Epidemiological evidence also suggests that other factors, such as race, smoking rate, and cancer registration, are unlikely to be the major factors responsible for the distinct differences in cancer rate. Lung cancer and colorectal cancer incidence rate in Fiji are only 7.8% and 5% of that in the U.S. respectively.
Our recent work demonstrates that kava can effectively suppress NNK- and B[a]P-induced lung tumorigenesis in A/J mice with no detectable adverse side effects. Mechanistically, kava suppresses NNK- and B[a]P-induced NF-kB activation in lung adenoma tissues, potentially responsible for its chempreventive activity. Currently we are optimizing kava’s chemopreventive efficacy through fractionation and establishing its long term chemopreventive efficacy against adenocarcinoma formation. In collaboration with Professor Daniel Gallaher, we also demonstrated that kava can reduce colorectal tumorigenesis and we are currently establishing its long-term chemopreventive efficacy and elucidating the chemopreventive mechanism.
PGG, decursin, and decursinol: in collaboration with Professor Johnny Lu, we are evaluating PGG, decursin, and decursinol as potential chemopreventive agents against breast cancer and lung cancer.
Cancer Therapies Rapid development of multiple drug resistance against current therapies is a major barrier in the treatment of cancer. Therefore, anticancer agents that can overcome acquired drug resistance in cancer cells are of great importance.
Antagonists against anti-apoptotic Bcl-2 family proteins and mechanism of apoptotic regulation. Tumors can develop drug resistance through over-expressing anti-apoptotic Bcl-2 family proteins, thereby evading apoptosis and leading to resistance to most cancer therapies. Our goal for this research is to develop a set of member-specific or organelle-specific small-molecule antagonists against different anti-apoptotic Bcl-2 proteins and to evaluate their potentials as selective cancer therapies and biological probes. Through molecular-modeling guided rational design, we have identified several candidates of varied selectivities among different anti-apoptotic Bcl-2 family proteins, including WL-276 and sHA 14-1 series. Current research focuses are SAR studies to improve the in vitro and in vivo anticancer efficacy and to elucidate the mechanism of these candidates to selectively kill drug-resistant cancer cells.
NF-kB inhibitors NF-кB proteins are a family of dimeric transcription factors. Under resting conditions, NF-кB dimers reside in the cytoplasm. Upon activation by free radicals, inflammatory stimuli, radiation, or chemical carcinogens, a 65-kDa unit (p65) of the NF-кB dimers translocates to the nucleus, where it activates the transcription of more than 200 genes, many of which can suppress apoptosis, stimulate proliferation, invasion, and metastasis. The activation of the NF-кB signaling pathway, therefore, may play a positive pivotal role in tumor promotion and progression. Inhibiting NF-kB activation therefore can potentially lead to successful cancer treatment. Our goal of this research is to develop small-molecule based NF-kB inhibitors and evaluate their potential as anticancer agents. Through high-throughput screening and natural product isolation, we have identified two sets of compounds with potent NF-kB inhibitor activities. The lead compounds are currently evaluated for their anticancer activities against lung cancer in vivo.