Our laboratory has broad interest in the application of basic molecular
biology to the study of disease-relevant issues. Major directions
include gene discovery, functional genomics and proteomics, gene regulation,
molecular immunology, cancer research and neuro-inflammation. These
divergent studies are incorporated into four major directions relying heavily
on cutting edge technologies including cDNA microarray, 2D gel-mass spectroscopy,
gene-ablation and RNA interference. These new approaches are integrated
with traditional approaches employed in molecular biology, biochemistry,
and immunology. Students typically are exposed to an enormous repertoire
of expertise and approaches.
1. Molecular Control of Immune Genes – We have focused on the genetic control of the broad family of class II Major Histocompatibility Complex (MHCII) genes. The master regulator, CIITA (class II transactivator), is absolutely essential for MHCII gene transcription, and its control is relevant to autoimmunity, vaccines and transplantation. It is not a DNA-binding protein, but controls MHCII genes by coordinating transcription factors at the promoter and modifying the chromatin structure. While its major targets are the family of MHCII genes, it also control a few other genes identified by cDNA microarray analysis. Divergent efforts are directed at understanding (a) the mechanism by which CIITA modifies chromatin, (b) the role of different isoforms of CIITA in transgenic mice and immune function, and (c) biochemical/biophysical and protein crystallization studies (with Ed Collins). Studies of CIITA in transplantation and models of multiple sclerosis are also ongoing.
Ting JP, Trowsdale J. Genetic Control of MHC Class II Expression. Cell. Vol 109. S21-33, 2002.
2. New Gene Discovery – Based on the structure of CIITA, we have found a large family of genes with similar structural motifs as CIITA, which we have termed the CATERPILLER (CARD, Transcription enhancer, Purine (R) binding, Pyrin, Lots of Leucine Rich Regions) gene family. This family now includes some famous members that are involved in several auto-inflammatory disorders, including NOD2 which provides a primary genetic link to Inflammatory Bowel Disease. Ongoing work has focused on five new family members. RNA interference, gene ablation, genomics and proteomics analyses are performed to understand the functions of these novel genes. Additionally, studies linking these genes to diseases such as arthritis, infections, inflammatory bowel syndrome, and vascular diseases are also ongoing.
Harton JA, Linhoff MW, Zhang J, Ting JP. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol. 2002 Oct 15;169(8):4088-93.
3. New Therapeutics and Biomarkers for Cancer – Combination and rational chemotherapies are crucial new approaches to cancer treatment. Taxol is a new but well-studied anti-tumor drug that inhibits microtubule disassembly, while MEK/ERK inhibitor impedes G1 cell cycle progression and is considered an experimental anti-cancer therapy. We have shown that paclitaxel induces MEK/ERK, which actually compromises and counters the anti-tumor efficacy of taxol. However, MEK/ERK inhibitors reverse this effect to promote more than additive apoptosis of tumor cells. Microarray analysis and 2-D gel coupled with mass spectroscopy were performed to understand the global effects of this drug combination on tumors and to identify new molecular targets in cancers. Functional analyses of these new potential biomarkers are currently conducted in the lab, using both animal models and patient samples. The efficacy of another new drug which has similar effects as taxol, but is resistant to the multi-drug resistant gene product, is also being analyzed in the laboratory.
MacKeigan, J, Collins TS, Ting JP. MEK inhibition enhances paclitaxel-induced tumor apoptosis. J Biol Chem. 275(50):38953-38956, 2000 (rapid communication).
4. The Role of CNS Inflammation and Microglia in Disease Progression and Resolution - Neurodegenerative and demyelinating diseases such as Alzheimer's, Parkinson's, Huntington's and multiple sclerosis exhibit inflammatory responses in the CNS. These responses include the induction of interleukins, tumor necrosis factors, nitric oxide, class I and II MHC antigens. To examine the role of neuroinflammation during disease progression and resolution, we have used a disease model where demyelination and remyelination can be predictably induced by feeding or withdrawing a neurotoxicant in the diet. Using mice with specific deletion in inflammatory genes, we found that many of these genes are not only crucial in disease progression (demyelination), but also in disease resolution (remyelination). A global view was provided with an cDNA microarray analysis of over 10,000 genes. Our results show wide-ranging changes in inflammatory genes, but also transcription factors, new apoptotic genes, and differentiation factors. Current research is focused on understanding how these genes affect demyelination and remyelination.
Arnett, HA, Mason, J., Marino, M, Suzuki, K, Matsushima,GK, and Ting, JP. TNFa signaling through TNFR2 promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neuroscience. 4(11):1116-22, 2001.
Jenny P.-Y. Ting