Our goal is to conduct research on inflammation. It is believed to be the underlying cause of most clinical disorders including autoimmunity, obesity, certain types of cancers, cardiovascular disease and neurodegenerative diseases.
Understanding the mechanisms of inflammation and approaches to prevent and treat inflammation may hold the key to successful promotion of health. We focus on understanding and treating autoimmune diseases against which there is no cure like lupus, arthritis and multiple sclerosis. Our center is supported by state-of-art Epigenomics Core, Microscopy and Imaging Core and Flow Cytomtery and Cell sorting Core.
Our Core Focus Areas
We strive to understand epigenetic regulation of inflammatory and autoimmune diseases by various plant-derived products.
Autoimmune and Inflammatory Disease
Autoimmune diseases are disorders in which the immune system, for reasons that are not clear, starts destroying an individual's own cells, tissues or organs by triggering a process known as inflammation. These diseases include more than 80 serious, chronic illnesses that involve almost every human organ system. Collectively, they affect 15-20 million people in the USA.
The main objective of our center is to pursue research in CAM that would test plant-derived compounds for their mechanism of immunosuppressive action and to test their efficacy in vivo against autoimmune diseases.
We have initiated a number of projects:
- Project 1 will investigate the effect of resveratrol, a compound found in many plant products including red grapes, on an experimental model for human multiple sclerosis (MS).
- Project 2 will test the efficacy of American ginseng on colitis and colon cancer.
- Project 3 will study the effect of dietary indoles on inflammation in the colon and colon cancer.
- Project 4 will test the efficacy of Sparstolonin B isolated from a Chinese herb, on hepatitis.
The center has created core resource facilities to screen the potential toxic and beneficial effects of plant-derived compounds on the immune system and to support its research activities. The center will create training opportunities for new investigators to pursue research on CAM and establish basis to initiate clinical trials on compounds that exhibit efficacy against specific autoimmune diseases.
CAM therapy against autoimmune and inflammatory disease
The underlying focus of the NIH CAM Center is to study the mechanisms by which plant/herbal products suppress the immune system and inflammation so that they can be used as preventive or therapeutic modalities in the treatment of autoimmune diseases. We are currently studying disease models that include multiple sclerosis, autoimmune hepatitis and colitis.
Autoimmune Hepatitis Disease
Nonalcoholic steatohepatitis (NASH), a common, often “silent” liver disease afflicts 2-5 percent of Americans. The major feature in NASH is fat in the liver, along with severe inflammation and damage. In this project we are studying how Sparstolonin B can be used to halt the transition from simple steatosis to NASH by virtue of its inhibition of some critical molecules involved in inflammation such as TLR2 and TLR4 in multiple liver cell types.
Study at NIH CAM Center
We are investigating the effects of a newly isolated Chinese herb-derived single compound, designated Sparstolonin B on hepatic inflammation. We have reported that Sparstolonin B effectively inhibited macrophage inflammation by selectively blocking toll-like receptors, TLR2 and TLR4 signaling via diminishing the recruitment of MyD88 to the intracellular domains of TLRs 2 and 4.
We will test the effect of Sparstolonin B on nonalcoholic steatohepatitis (NASH), a common, often “silent” liver disease that afflicts 2-5% of Americans. The major feature in NASH is fat in the liver, along with severe inflammation and damage. Our central hypothesis is that Sparstolonin B can halt the transition from simple steatosis to NASH by virtue of its inhibition of TLR2 and TLR4 inflammatory signaling in multiple liver cell types.
Colitis (ulcerative colitis)
Ulcerative colitis is an inflammatory bowel disease (IBD) wherein the cells lining the walls of the rectum and colon develop sores and ulcers due to an inflammatory process initiated by the cells of the immune system. This inflammatory reaction leads to damage to the lower digestive tract leading to bleeding and signs of frequent bowel movement or diarrhea. Approximately 4 million people worldwide have the disease and are at increased colon cancer risk. We are testing the efficacy of various botanicals, such as Indoles and Ginseng, to treat colitis.
Study at the Center
The center is currently investigating the mechanisms by which American ginseng, a natural herb and a putative anti-oxidant, suppress the inflammatory response associated with colitis. We are also studying the effect of indoles found in green cruciferous vegetables in preventing colitis and colon cancer.
Multiple sclerosis (MS) is an autoimmune disease in which the body's immune system attacks the cells of the brain. MS is a neurodegenerative autoimmune disease that affects approximately 350,000-500,000 people in North America alone and the incidence is higher in women than men. We are currently investigating the effect of resveratrol on MS.
Study at the NIH CAM Center
Our studies are aimed at addressing the mechanism underlying use of CAM therapy in the treatment of MS. We are testing the potential of grape-derived chemical, resveratrol in the treatment of MS using murine EAE models. We will be testing the central hypothesis that resveratrol treatment is effective against EAE through multiple pathways that include induction of apoptosis in myelin-specific T cells, suppression of Dendritic Cell functions, decreased T cell infiltration in the CNS due to down-regulation of homing receptors such as CD44 and upregulation of T regs. We are also studying epigenetic pathways through which resveratrol controls inflammation in the brain.
Epigenetic pathways in resveratrol-induced amelioration of neuroinflammation
Principal Investigator Prakash Nagarkatti
In this project, we will test the hypothesis that resveratrol (RES) activates aryl hydrocarbon receptor (AhR) and/or estrogen receptor (ER) leading to induction of epigenetic pathways including DNA methylation and histone methylation/acetylation as well as miRNA regulation, which promote the differentiation of a unique type of suppressor cells called Myeloid-Derived Suppressor Cells (MDSCs) that ameliorate neuroinflammation seen in experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS). We will test RES-mediated epigenetic regulation of genes G-CSF, CD11b, Gr-1, Arg1 and iNOS in hematopoietic progenitor cells and MDSC.
Epigenetic regulation of Nrf2 signaling pathway in American Ginseng-mediated suppression of inflammation in the colon
Principal Investigators Lorne Hofseth and Taixing Cui
In this project, we will test the central hypothesis that nuclear factor erythroid-2 related factor 2 (Nrf2), a central endogenous regulator of intestinal antioxidant and phase 2 defenses, is a critical mediator of American ginseng (AG)-induced suppression of intestinal inflammation and that AG regulates its activity through epigenetic pathways. We will test the efficacy of AG in three mouse models of colitis and colon cancer (chemical and/or bacterial infection-induced models). We will delineate mechanisms by which AG and AG-Fraction V regulate Nrf2 signaling specifically on the Keap1:Nrf2 interface as well as examine epigenetic alterations including miRs that control Nrf2 and Keap1 genes.
Indole-mediated epigenetic regulation of T cells in colitis
Principal Investigator Mitzi Nagarkatti
In this project we will test the central hypothesis that treatment with indole-3-carbinol (I3C) or diindolylmethane (DIM), activates aryl hydrocarbon receptor (AhR), leading to reciprocal regulation of proinflammatory T cells versus anti-inflammatory T cells via epigenetic pathways including DNA methylation and histone methylation/acetylation as well as miR induction, leading to suppression of inflammation in the colon. We will investigate how I3C/DIM activate AhR leading to suppression of proinflammatory Th1/Th17cells and induction of Tregs/Th2 cells via epigenetic regulatory mechanisms using 3 models of colitis, 2 chemical and 1 microbial infection model. We will test epigenetic regulation of FoxP3, IL-17 and IFN-γ.
Sparstolonin B as a TLR antagonist in suppression of liver inflammation through epigenetic mechanisms
In this project, we will test the central hypothesis that Sparstolonin B (SsnB), a novel compound, isolated from Chinese herb Sparganium stoloniferum can halt the transition from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) by virtue of its ability to inhibit TLR2 and TLR4 signaling in multiple liver cell types through epigenetic regulation.
We will test our hypothesis using 3 mouse models of NASH:
- Western diet fed apoE-/- mice administrated with one dose of LPS (LPS as a second hit and a TLR-4 ligand)
- A chronic environment-linked NASH model (A CYP2E1 substrate for oxidative stress as a second hit)
- A more established model by feeding wild type C57BL/6 mice with a methionine- and choline-deficient diet (MCD) which causes the transition from benign steatosis to steatohepatitis. (Dietary interactions as a second hit.). We will test epigenetic regulation of TLR-2, TLR-4 and MyD88 genes.