I am a surgeon-scientist. My clinical interests are caring for patients with benign and malignant liver disease. My research interests are studying the immunological changes in acute chronic liver disease. More than 75% of my time is spent in the laboratory. My primary career goal is to become an independent investigator in liver immuno-pathology and to be able to translate my bench-work to clinical trials for my patients. My secondary goals are to inspire other young physicians to pursue investigative careers. I have a wonderful mentoring system set-up for my early career. My mentor (Alan Frey) is a leading immunologist and my co-mentor (Bruce Cronstein) is a physician who is a noted authority on the pathogenesis of chronic liver disease. I am fortunate to have a very close personal relationship with both my mentor and co-mentor. My proposed training program is enhanced by limited didactic seminar-style coursework in basic science (years 1 and 2) to enhance my understanding of molecular pathogenesis and a Masters of Science in Clinical Investigation program with a focus in Translational Medicine (years 3 and 4). The latter is a program that is directed by my co-mentor and its aim is to train clinician-scientists in the skills necessary to translate scientific discoveries to clinical settings. The research environment at NYU is extremely supportive for this work. As a highlight, we currently have a multidisciplinary liver-interest group that meets weekly to discuss clinical, basic science, and translational concepts in liver disease. My research proposal aims to study the role of liver dendritic cell activation in the pathogenesis of hepatic fibrosis. The pathogenesis of liver fibrosis is complex and our understanding of the cellular and biochemical factors underlying its development are still rudimentary. Hepatic stellate cells (HSC) are the primary producers of the extracellular matrix in liver fibrosis. After hepatic injury, a diverse interplay of cell types including immune-competent cells, such as T cells and kuppfer [sic] cells, produce an array of cytokines including IL-6, CCL21, TNF-(, and TGF-( which result in HSC activation, extracellular matrix deposition, and eventually progresses to liver fibrosis and cirrhosis. Dendritic cells (DC) are the primary antigen presenting cell in the immune system and initiate innate and adaptive immunity. However, liver DC represent a distinct phenotype that are [sic] prone to induce tolerance rather than immunity. In fact, the inability of liver DC to initiate effective immunity to antigen is a primary factor contributing to both oral tolerance and the acceptance of hepatic allografts with little immune-suppression. While normal liver DC induce T cell anergy and are poor initiators of inflammation, the function of DC in states of hepatic fibrosis - and their contribution to the fibrotic process itself - has not been previously studied. Our preliminary data show that in hepatic fibrosis, liver DC are remarkably effective at engaging both innate and adaptive immunity and;moreover, DC are entirely responsible for the elevated hepatic cytokine milieu in the fibrotic liver. The increased inflammation and enhanced stimulation of T cells and NK cells by liver DC in liver fibrosis is contingent on their elevated production of TNF-(. Based on these observations, we postulate that in states of hepatic fibrosis there is a fundamental shift in liver DC function from weak immunogenicity and initiation of tolerance to potent induction of effector cell immunity and inflammation. Furthermore, we postulate that this shift in DC function toward immunogenicity underlies the inflammatory cascade in the fibrotic liver and is a critical component to the pathogenesis of hepatic fibrosis.
Specific aims of this study are (i) To determine whether liver DC convert from inert inducers of tolerance to potent immune-stimulators in liver fibrosis, (ii) To determine the contributory role of DC in the pathogenesis of fibrosis and their direct role in HSC activation, (iii) To determine whether blockade of the immunogenic function of liver DC can mitigate the fibrogenic response to liver injury. Our expected findings will suggest that further studies aimed at countering the effects of liver fibrosis must account for the central role of DC. We expect that our work will also broach a new area of experimental therapeutics in the treatment of hepatic fibrosis.
In USA, 27,000 people die annually from liver cirrhosis. Worldwide, liver fibrosis and cirrhosis is the third most common cause of death after heart disease and cancer among people aged 45 to 65. There is no currently available effective therapy for liver fibrosis. Furthermore, the cellular and biochemical pathogenesis of hepatic stellate cell activation in hepatic fibrosis is poorly understood. Targeting dendritic cells in the pathogenesis of liver fibrosis would have wide clinical relevance for new experimental therapeutics.
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| Rehman, Adeel; Hemmert, Keith C; Ochi, Atsuo et al. (2013) Role of fatty-acid synthesis in dendritic cell generation and function. J Immunol 190:4640-9 |
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