There are three major areas of research in my laboratory.
Project 1. Role of Fcgamma receptors, autoimmunity and atherosclerosis.
My laboratory studies the regulation of inflammatory responses in the vasculature focusing on immune aspects of atherosclerosis. We are particularly interested in how autoantibodies against oxidized LDL lead to chronic inflammatory states. The major milestones in this project include a) discovery of activating Fcg chain signaling as a major contributor of oxLDL-IC induced macrophage activation. b) Deficiency of activating FcgRs in apoE-/- background inhibits Th17 and increasing T-regulatory cells, resulting in attenuation of atherosclerosis. c) All three activating FcgRs (RI, III, and IV), contribute independently to the progression of atherosclerosis. d) Contrary to our expectation, mice lacking inhibitory FcgR, apoE-FcgRIIb-/-B6 (congenic to C57BL/6 background) did not show exacerbated atherosclerotic lesions compared to apoE-/- mice. FcgRIIb polymorphism has been implicated in systemic lupus erythematosus (SLE, lupus). Moreover type-I interferon response genes are upregulated in FcgRIIb-deficiency in lupus prone mice, and C57BL/6 mice carrying FcgRIIb loci from lupus-prone mice (NZB, 129/sv), prompted us to investigate the role of FcgRIIb in lupus-induced atherosclerosis. We have an exciting finding that lupus induction exacerbated atherosclerosis in apoE-FcgRIIb double knockout mice compared to apoE-/- mice treated similarly. This led to the current proposal that under systemic lupus erythematosus (SLE, lupus) condition, increased incidence of atherosclerosis could be mediated by immune complex interactions at the vascular site through FcgRs. Moreover, enhanced type-I interferon signaling, implicated in lupus and atherosclerosis progression, could be a possible mechanism for the exacerbated lupus-induced atherosclerosis in FcgRIIb-deficient mice. My laboratory is studying the role of lupus autoantibodies in mediating inflammatory response at the vascular site via FcgR interactions, using the mouse model and samples from patients with lupus.
Project 2. Chlamydial genital infection and progression of atherosclerosis.
In the second project, we are exploring the causal link between genital infections priming vasculature to promote atherosclerosis later in life. Genital chlamydial infection is the most common sexually transmitted bacterial infection in the US. However, there has been no study investigating if genital Chlamydia trachomatis infection primes the host for accelerated atherosclerosis. To investigate a possible link between genital chlamydial infection and atherosclerosis, atherosclerosis prone apoE -/- and LDLR -/- mice fed a high fat diet were infected genitally with Chlamydia. In both the hyperlipidemic models, we made the novel observation that infected mice developed significantly increased atherosclerotic lesions after resolution of chlamydial infection, in comparison to the uninfected mice. Based on these findings, we are testing the hypothesis that “systemic inflammation induced by genital chlamydial infection exacerbates atherosclerotic lesions”. We anticipate that the results obtained from these studies will determine the specific mechanism of increased vascular pathology observed after genital chlamydial infection in the mouse model. Moreover, the association between genital chlamydial infection and atherosclerosis in the mouse model will validate a need for future epidemiology studies in this area.
Project 3. Gestational soy exposure and prevention of atherosclerosis.
The third project centers on the global issue of how dietary factors modulate the immune system to prevent chronic inflammatory diseases including atherosclerosis. Epidemiological reports suggest that cardiovascular incidence is lower in Asian population. It is plausible that the diets such as soy and rice may modulate the immune system, thus preventing atherosclerotic lesions. Our findings showed the progression of atherosclerotic lesions were strikingly reduced in soy protein fed hyperlipidemic animal models. There are two major components with potential bioactivity in soy diet or soy protein isolates: phytochemicals such as isoflavones associated with soy protein, and peptides generated from two of the major soy proteins such as b-conglycinin (or 7S globulins) and glycinin (or 11S globulins). We have recently identified isoflavone-free soy protein inhibits the progression of atherosclerosis by blocking inflammatory cytokine/chemokine responses and inflammation induced VCAM-1 expression. Interestingly, maternal hypercholesterolemia has been implicated with a higher incidence and earlier onset of atherosclerotic lesions in neonatal offspring. Currently, we are investigating if and how gestational exposure to soy protein isolate diet primes the vessel wall to attenuate development of atherosclerosis in adult life of F1 offspring. Specifically, we are studying the effect of gestational dietary exposure of soy or soy derived compounds in preventing chronic inflammatory diseases such as atherosclerosis.
List of publications from PubMed