Medical School Hotline

Mission

The mission of the Department of Cell and Molecular Biology (CMB) and the CMB Graduate Program at the John A. Burns School of Medical is to provide an outstanding environment for excellence in research and education in Cell and Molecular Biology and related biomedical disciplines.

Overview

The CMB Department (http://jabsom.hawaii.edu/departments/cmb/) and the CMB Graduate Program (http://www.hawaii.edu/cmb/CMB/Home.html) at the John A. Burns School of Medicine, University of Hawai‘i (UH) at Manoa are comprised of a collection of multidisciplinary, outstanding faculty, graduate students, postdoctoral fellows, and technical and administrative support staff engaged in a highly diverse array of research. Areas of research focus include biochemistry, cell and molecular biology, ecological and evolutionary biology, endocrinology, genetics, immunology, neurobiology, reproductive biology, cancer biology, infectious diseases, and cardiovascular research. Funding supporting this research derives from the National Institutes of Health, the American Heart Association, the Alzheimer's Foundation, the Michael J. Fox Foundation, pharmaceutical companies, the Hawai‘i Community Foundation, and the State of Hawai‘i. Undergraduates and high school students also participate in research projects under the guidance and training of department members. Faculty in the CMB Department include 7 Full Professors, 3 Associate Professors, 2 Associate Research Professors, 4 Assistant Research Professors and 2 Junior Researchers (postdoctoral fellows). The Department brought in over $8 million in extramural funding in fiscal year 2014 and in addition to their research endeavors, faculty participate extensively in medical, graduate, undergraduate, and high school education. Grants held by faculty in the Department support numerous research facilities in Kaka‘ako, UH Manoa, and the Queen's Medical Center. In addition, an $18.4 million NIH IDeA Network of Biomedical Research Excellence (INBRE) grant directed by Dr. Robert Nichols, is focused on building a research pipeline in the State of Hawai‘i and supports junior faculty and undergraduate research training at the UH Hilo, Chaminade University of Hawai‘i, Hawai‘i Pacific University, and the UH Community Colleges. An $11 million NIH Research Centers in Minority Institutions (RCMI) grant entitled Bioscience Research Infrastructure Development for Grant Enhancement and Success (BRIDGES), directed by Dr. Marla Berry, is devoted to building the research infrastructure across the UH.

Alzheimer's disease. Dr. Robert Nichols' laboratory is investigating the earliest stage in the development of Alzheimer's disease. The focus is on neurotoxicity induced by a spike in one pathological component, beta amyloid, early in the disease process. Recent work in the laboratory has demonstrated that specific target receptors sensitize neurons to the neurotoxicity induced by beta amyloid.¹ To investigate the structural basis of this sensitization, a consortium was formed to study the synaptic actions of beta amyloid peptides using a multiplicity of approaches (imaging, electrophysiology, and behavioral testing) supported by core facilities. The consortium includes CMB faculty members: Drs. Todorovic, Bellinger, and Nichols (PI), and several trainees (PhD students and postdoctoral fellows). This work has led to the discovery of neuromodulatory peptide fragments from beta amyloid with potential neuroprotective activity.² The beta amyloid peptide fragments are being developed as possible new therapeutics for Alzheimer's disease.

Myopathies and Parkinson's Disease. Research in Dr. David Jameson's laboratory is focused in two major areas, the functions of dynamins in diseases including myopathies and mutations implicated in Parkinson's disease. Studies on the role of the large GTPase, dynamin, in endocytosis and elucidation of the defects in mutated dynamins have important implications in diseases such as Centronuclear Myopathy. A recent grant from the Michael J. Fox Foundation, awarded to Dr. Nicholas James and the first such award at the UH, supports investigation of how mutations in the protein LRRK2, implicated in Parkinson's disease, influence the self-association and activity of this kinase.³ Dr. Jameson has also authored a textbook entitled “Introduction to Fluorescence” which is receiving outstanding reviews.

Modulation of traumatic memories by JNK signaling pathway - relevance for anxiety disorders. Human studies demonstrate that the c-Jun NH2-terminal kinase (JNK) signaling pathway is associated with neuropsychiatric disorders. Recent studies in Dr. Cedomir Todorovic's laboratory for the first time demonstrated that exposure to stress causes activation of JNKs in the hippocampus, and impair conditioned fear and long-term potentiation. They also demonstrated an enhancement of conditioned fear after pharmacological inhibition of JNKs under baseline conditions. Using transgenic approaches, they provided evidence that JNK2 and JNK3 isoforms are responsible for stress-induced deficit of acquired fear, while JNK1 isoform regulates baseline fear memory.^4,5 In addition, they provided evidence that elimination of fear memories includes NMDA glutamate receptor-stimulated JNK3 activation, and removal of AMPA receptors from the synapses. These results provided mechanisms responsible for fear memory formation and its elimination that may provide effective prevention and treatment of anxiety disorders.

Cardiovascular calcification. Pathological mineralization of the vasculature occurs during aging and in several common acquired conditions, such as diabetes, hypercholesterolemia, chronic renal failure, and certain genetic disorders. The ABCC6 protein is primarily found in liver and kidneys and exports unknown substrates that mediate the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by ENPP1 and NT5E. Adenosine and PPi potently inhibit calcification. The physiological relevance is that ABCC6 generates the majority of the PPi released from liver, and 60% of the PPi in plasma. ABCC6 dysfunction is the primary cause of ectopic calcification in pseudoxanthoma elasticum,^6–8 some cases of generalized arterial calcification of infancy, and β-thalassemia. These diseases serve as models to enhance our understanding of more common conditions. Drs. Olivier Le Saux and Christopher Brampton are currently developing a pilot clinical trial and studying other physiological roles for ABCC6 related to cardiac function and atherosclerosis.

Cardiovascular disease - On the way from the Bench, to the Bedside. Dr. Alexander Stokes' laboratory has identified a new target and set of effective therapeutic compounds for the treatment and prevention of heart failure. Makai Biotechnology LLC is licensing this intellectual property, and partnering with UH, which holds an interest in Makai Biotechnology. The new treatment method focuses on the regulation of the ion channel TRPV1. This ion channel is best known for being activated by capsaicin, the hot component of chili peppers. The Stokes lab recently published pre-clinical data that show that inhibition of TRPV1 with a small molecule compound can protect the heart from the pathological and functional changes associated with cardiac hypertrophy, heart failure and associated pathologies.^9,10 The Stokes Lab and Makai Biotechnology are optimistic that therapy can be developed to help treat the large number of people suffering from heart failure.

Mitochondrial Etiology of Metabolic Diseases. Dr. Mariana Gerschenson's laboratory studies the mitochondrial etiology of adult and pediatric diseases. Recent studies have been on HIV and non-HIV insulin resistance (IR), diabetes, lipodystrophy, and cardiovascular disease in Hawai‘i and in multi-site cohorts across the United States. The research focuses on studying genetic and functional mechanisms. HIV lipodystrophy has been shown to be due to mitochondrial RNA transcription alterations and not mitochondrial DNA depletion.¹¹ Furthermore, mitochondrial specific oxidative stress, in the form of 8-oxo-guanine, in peripheral blood mononuclear cells (PBMC) is associated with HDL function in adult HIV patients and is associated with the pathogenesis of cardiovascular disease.¹² Pediatric HIV patients with IR have decreased PBMC mtDNA and decreased respiration and ATP synthesis compared to IR negative children.^13–14 These mechanistic studies will assist in the diagnosis, prevention, and treatment of metabolic/cardiovascular diseases.

The University of Hawai‘i Biorepository - A resource for translational studies. The UH Biorepository is operated by CMB faculty members Dr. Alexander Stokes (Director) and Dr. Joshua Astern (Manager), and facilitates an array of biomedical research projects in Hawai‘i, nationally, and internationally. The Biorepository contains three major resources. The Human Reproductive Biospecimen Repository is supported by the RMATRIX grant from the NIH, awarded to Dean Jerris Hedges. This resource contains donated samples and de-identified clinical information from over 9,000 women and their newborns. The Comprehensive Human Organ and Tissue Bank is supported by the aforementioned RCMI-BRIDGES grant and contains primary human tissues from multiple organs. The INBRE III Biorepository and In Vivo Model Resource is funded by the aforementioned INBRE grant. This resource was designed to provide researchers at non-UH-Manoa institutions access to biomedical samples and services including training in biorepository techniques, and serves as a consultation resource to access and implement in vivo models. Projects utilizing the UH Biorepository have focused primarily on the effects of genetics, obesity, diabetes, infection, and immune function on birth outcomes, cardiovascular biology, and liver function. The UH Biorepository continues to procure valuable samples and data for use in research projects, publications, and grant applications. For more information please visit: http://uhbio.jabsom.hawaii.edu.

Selenium: inflammation and immunity. Dr. Peter Hoffmann's laboratory has long been interested in revealing mechanisms by which dietary selenium influences inflammation and immunity. Their studies have shown that levels of selenium intake change the redox status of immune cells and this dramatically affects their activation, proliferation, differentiation, and function. In addition to redox status, changes in selenium status can directly affect expression levels of individual selenoproteins in a wide variety of immune cells. The laboratory is currently dissecting the molecular interactions of selenoprotein K with other cellular proteins and the precise biochemical mechanisms by which this particular selenoprotein regulates immune cell function. Some of the diseases on which our work focuses include inflammatory bowel disease, different types of cancers, immunity to infectious diseases, and others.

Selenium and metabolic disorders. Drs. Lucia Seale, Marla Berry, and Matthew Pitts are investigating the role of dietary selenium in development of metabolic disorders. Several selenoproteins have been shown to act in maintenance of proper metabolic function and energy balance in laboratory and clinical studies. Disruption of selenium recycling results in development of obesity and symptoms of diabetes in animal models,¹⁵ and excess selenium results in a trend toward development of type 2 diabetes in humans.¹⁶ This effect was found to be gender specific in both clinical trials in humans and recent studies in mice, in both cases being observed only in males. Dr. Berry was recently awarded an NIH grant to investigate the reasons for this gender specificity.

Selenium and neurological function. Drs. Pitts and Berry are studying the roles of selenium in neurological function. Their studies reveal that disruption of both selenium transport to the brain and recycling of dietary selenium results in severe impairment of neurological motor function, seizures and death.¹⁷ These effects are also more pronounced in males than females, and the reasons for this difference are under investigation. Dr. Frederick Bellinger's group is studying the role of selenoproteins in neurodegenerative disorders. They have found correlations of selenoprotein expression with neuropathology in Alzheimer's disease¹⁸ and Parkinson's disease,¹⁹ suggesting possible roles in mitigating these disorders. Current research is investigating the actions in Alzheimer's disease of sodium selenate, an exciting potential therapy currently being investigated in a phase II clinical trial. Additional findings include discovering changes in antioxidant selenoprotein expression and function resulting from exposure to methamphetamine.²⁰

Ecological and Evolutionary Genetics. Dr. Rebecca Cann's long-term project at Hakalau Forest National Wildlife Refuge, island of Hawai‘i, has generated concern over the future of native Hawaiian forest birds.^21–25 Habitat management to restore the high elevation forest for endangered birds has also had negative consequences, with population sex ratio changes due to loss of breeding females, a year-long extension of molt, the explosive eruption of chewing lice, and invasive alien birds. Populations have crashed from intense competition with the invasive Japanese White Eye. Dr. Cann also explores the potential emergence of tolerance to avian malaria within a small population of amakihi on O‘ahu, and models climate change to show how high-elevation human populations may be at increased risk from enhanced mosquito movement. Her new Sri Lankan research examines an emergent hybrid swarm of exotic woodpeckers, where climate change is blurring boundaries between species.

Diversity and Threat of a Superbug in Hawai‘i. Dr. Steven Seifried's laboratory studies Staphylococcus aureus. The resistant bacterial pathogen is sometimes called MRSA. Dr. Seifried and colleagues characterized the strain types of S. aureus found in Hawai‘i's natural, clinical, and public environments. These strains represent much of the world's phylogenetic diversity; brought to Hawai‘i by global travelers. The laboratory developed methods and found a low prevalence and fleeting persistence of S. aureus in Hawai‘i's beach waters. Transient concentrations of the bacterium shed from beach users yield a low risk for seawater-associated exposure to S. aureus, although other human activities at the beach can heighten risk of exposure. Individual bacterial isolates are examined to better understand the transition from benign commensal carriage to potential lethal pathogen. Whole genome sequencing is also used to investigate why some strains are sensitive to most antibiotics, while very closely related strains demonstrate dangerous multiple antibiotic resistance.

Community Impact — The Innocence Project. Dr. David Haymer has served for a number of years as the DNA consultant for the Hawai‘i Chapter of the Innocence Project. The Innocence Project is a national organization that investigates cases where there is the possibility of a wrongful conviction of an innocent person. The Hawai‘i Chapter is headed by Professor Virginia Hench of the Richardson School of Law at UH, and Dr. Haymer is brought in when their investigations include the use of DNA evidence. In March of 2013, the local project had its first major breakthrough case when the conviction of a Maui man, who had been in jail for 20 years on a rape charge, was set aside primarily based on new DNA evidence.

The Future. The future efforts of the department will focus on continuing to build on our strengths and expertise through increasing interactions and collaborations with other units at JABSOM, UH and elsewhere, advancing our efforts in biotechnology, increasing the entrepreneurial atmosphere of the department, and recruitment of faculty with expertise in bioinformatics, genomics, proteomics, metabolomics, and other multidisciplinary areas that will increase our competitiveness in the global research and education community.