2008-09 Academic Federation Innovative Development Awards Recipients

Michael George
Assistant Research Microbiologist
MED: Medical Microbiology and Immunology
Summary of Research:
In human immunodeficiency virus (HIV) infected patients, debilitating secondary infections from opportunistic pathogens often develop within the oral cavity (REFS). Host vulnerability appears to be linked to deterioration of the epithelial layer, and while the molecular mechanisms remain unknown, epithelial pathogenesis is likely to initiate early in infection, prior to the appearance of clinical atrophy. Due to the difficulty in acquiring adequate tissue samples for in vivo studies, however, comprehensive investigations into the oral biology of HIV infection have been limited to date and it is increasingly clear that experimental progress will require effective utilization of in vitro models and innovative biotechnologies. The research proposed is designed to develop a miniaturized co-culture system for testing the hypothesis that pathogenesis of the oral epithelium during HIV infection occurs, in part, through disruption of normal interactions with oral mucosal lymphocytes. In recent studies of simian immunodeficiency virus (SIV) infection in the rhesus macaque model, Dr. George has demonstrated that, like the gut mucosa, high levels of SIV replication and severe CD4+ T cell depletion occur in the oral mucosa early in primary stage infection (1). The proposed studies seek to utilize pioneering technology to investigate how oral epithelial cell growth, maturation, and defense response functions are affected by the presence of HIV infection. Findings from these preliminary studies will be utilized in submission of an R21 category grant application to the National Institutes of Health in January, 2009.

Shuzhen Hao
Assistant Project Scientist
VM: Anatomy, Physiology and Cell Biology
Summary of Research:
Sensing of luminal contents by the gastrointestinal (GI) mucosa via specific sensors, including G-protein coupled receptors and activation of intrinsic and extrinsic primary afferent neural pathways, plays a critical role in the regulation of physiological and pathological digestive functions. Bitter taste receptors (T2Rs) and their G-protein subunits (Gagustducin and Ga-transducin) that signal bitter taste on the tongue have recently been shown to be expressed in the GI mucosa of both human and rodents. However, their functions are unknown. Preliminary data in rats suggests that these receptors are functional and ligands for these receptors activate endocrine cells including serotonin (5-HT) releasing cells and visceral afferent pathway. The hypothesis to be tested is that activation of T2Rs in the gut stimulates activation of both intrinsic and extrinsic neural pathways is mediated via release of 5-HT. The specific aims are: (a) To determine that activation of T2Rs in the gut activates extrinsic neural pathways via activation of 5-HT3 receptors on primary afferent nerve terminals; (b) To determine that activation of T2Rs induce release of 5-HT from the gut and from BON cells, a cell model of enterochromaffin cells; (c) To determine that activation of T2Rs stimulates intestinal fluid secretion in the gut and further is mediated by 5-HT through acting on 5-HT3 and 5-HT4 receptors. The successful completion of these experiments will provide information on the role of T2R expression in the gut and will provide an opportunity to determine their regulation and role in physiological or pathophysiological events in the GI tract.

Christoph Lossin
Assistant Professional Researcher
MED: Neurology
Summary of Research:
Myotonia congenita is a muscle condition where patients experience painless cramps upon initiating movements after rest. Interestingly, the muscle relaxes after several repetitions of the same movement and the individual becomes effectively asymptomatic (warm-up phenomenon). There are two types of the condition whose main distinguishing criterion is the inheritance pattern: Thomsen’s type myotonia is passed on autosomal dominantly, while Becker’s myotonia is a recessive trait. Becker’s myotonia is usually more severe, gives rise to muscular hypertrophy, and it may also have quickly-passing muscular weakness associated with it that is not seen in Thomsen’s myotonia. Ion channel dysfunction lies at the heart of the condition. This had been long suspected in the past, but first molecular evidence was produced when the skeletal muscle chloride channel gene CLCN1 was shown to be mutated in myotonia congenita animal models and patients. Electrophysiological analysis of associated amino acid exchanges demonstrated loss-of-function either by shifts in the voltagedependence of activation or by alterations in the ion selectivity of the channel.

Brenda McCowan
Associate Professional Researcher
VM: Population, Health & Reproduction
Summary of Research:
The objective of this study is to examine the effects of positive reinforcement training (PRT) on the development of nursery-reared, infant rhesus macaques, and its potential usefulness to improve behavioral and physiological development and thus to enhance both individual welfare and research model validity. Rhesus macaques were chosen as our subjects due to their widespread use in biomedical research laboratories, and the prevalence of abnormal behaviors in their activity budgets. The California National Primate Research Center (CNPRC) supports a colony of 5,000 monkeys, of which approximately 15- 20% are nursery reared. Our rationale is that PRT, if useful as an enrichment tool during development in promoting a more species typical developmental trajectory, will be important for enhancing nursery-reared infant rhesus monkeys with respect to both their welfare and as better research models for biomedical research. Results from this study will be used to inform decisions about primates’ optimal environments for increased welfare, thereby meeting or exceeding the Animal Welfare Act’s mandate. Results can also be used to enhance infrastructure for research by improving behavior management practices in research facilities that house nonhuman primates, therefore providing investigators with a better research model. Additionally, results of this study will be used to help policy makers and behavioral managers develop guidelines for the treatment and welfare of captive animals.

Yajarayama Tang-Feldman
Research Specialist
MED: Internal Medicine
Summary of Research:
Atherosclerosis is a chronic multifactorial inflammatory disease of the medium and large arteries, and the major cause of myocardial infarction and stroke. Multiple studies suggest an association between cytomegalovirus (CMV) infection and atherosclerosis. In the immunocompetent host, response to CMV infection is characterized by the production of pro-inflammatory cytokines. These cytokines, particularly IL-6, induce over expression of C-reactive protein (CRP), an acute phase protein which might accelerate the progression of atherosclerosis.

Our long term goal is to elucidate the mechanisms by which CMV infection may contribute to atherogenesis, and to use these findings to promote development of preventive or therapeutic alternatives. We hypothesize that: 1) CMV may contribute to atherosclerosis by infecting heart tissue and inducing both a systemic and local inflammatory responses; 2) CMV infection induces the stimulation of immune cells with the production of cytokines, chemokines and adhesion molecules that in turn induce the production of CRP. This hypothesis is supported by: a) CMV DNA has been detected in the cells of the vascular wall; b) pro-inflammatory cytokines are produced in response to CMV; and c) CMV seropositivity and elevated levels of CRP are associated with increased risk of atherosclerosis. No studies have correlated MCMV infection and up-regulation of CRP expression, and their role in atherogenesis. We propose to study our hypotheses in our well characterized mouse model of murine CMV (MCMV).

The specific aims of this proposal are: 1) To establish an association between MCMV infection, CRP and development and/or exacerbation of atherosclerotic lesions using the apolipoprotein E-/- (Apo E-/-) mouse model of atherosclerosis. 2) To identify synergistic mechanisms by which MCMV and CRP contribute to the development and/or progression of atherogenesis

Heiko Wittmer
Assistant Adjunct Professor
Wildlife, Fish & Conservation Biology
Summary of Research:
Conservation Biology by definition is an applied science and as such relies on data collected in the field to develop management strategies for threatened species and/or populations. Funding for field based research, however, has been increasingly difficult to obtain because there often is great reluctance to pay for new projects without strong indications that such information is essential to direct future management. This places researchers into a position where they need to approach possible funding agencies with preliminary data in order to successfully argue for the necessity of future grants. The objective of this proposal is to obtain funding to initiate a research project and generate preliminary data which will then be used to apply for funding required for a more detailed, long-term study. The primary extramural agency targeted is the California Department of Transportation (CALTRANS) with additional funding also being sought by the California Department of Fish & Game (DFG). Collisions between large vertebrates and vehicles along roadways are an increasing concern, not only because of ecological consequences to animals, but also because of associated economic and social costs (Forman et al. 2002, Bissonette et al. 2008). For example, 4% (or 247,000) of motor vehicle collisions in the United States reported to the police in 2000 involved hitting a deer (National Highway Traffic Safety Administration 2000). These deer related accidents resulted in >25,000 injured drivers (c.f. Bissonette et al. 2008). Despite these high costs to society, transportation agencies across the country have been reluctant to implement costly mitigation strategies to reduce the number of animal-vehicle collisions.