Chronic inflammation plays a major role in the onset and progression of many diseases. One of the major players and mediators of inflammatory processes are a family of transcription factors known as NF-?B. We are proposing to study the molecular mechanisms involved in inflammation and their consequences to disease. We plan to undertake: A kinome-wide RNAi screen for novel mediators of the NF-?B pathway. By using shRNA lentiviral library and high-throughput screening (HTS) technology we have identified 30 kinases, which can effect NF-?B activity upon stimulation by external agents. To gain insight into the biology of the fully validated kinases that modulate the activity of NF-?B pathway, we will undertake extensive biochemical and biological analysis of the top candidates involved in modulating NF-?B pathway. Glucocorticoid receptor repression of NF-?B: Identification of novel molecular mechanisms. Glucocorticoids are among the strongest anti-inflammatory agents and one of the most common forms of treatment to suppress inflammation;however many negative side effects can occur with long term use. We have identified p53 as a candidate gene whose product is required for induced suppression of NF-?B activity by glucocorticoid. We have also identified about 25 kinases that are needed in glucocorticoid induced repression. Inflammation and diabetes: Role of Tlr4 in macrophages. Insulin resistance is a major metabolic defect in obesity, and is associated with increased risk of various diseases. Macrophages are an important modulator of inflammation through their capacity to secrete a variety of proinflammatory chemokines and cytokines. We hypothesized that knock-out of Tlr4 signaling in hematopoietic-derived cells (which includes macrophages), would reduce obesity-related increases in macrophage infiltration and inflammation and subsequently prevent in vivo insulin resistance. We will knock down Tlr4 either biologically or use an antagonist and see if the animals are now insulin sensitive. Inflammation and cancer: The link between inflammation and cancer is well established and the variety of new tools available will allow us to molecularly dissect this connection, leading to therapeutic entities. We propose to study the role of inflammation in the context of local inflammation and the inflammatory milieu surrounding the tumor. Specifically we propose to take advantage of our recent mouse model to generate gliomas in immune competent mice. We will create conditions of inflammation both in the tumor and in the surrounding milieu to understand its role in tumor formation and progression. P53 and IKK2: We have found that IKK2, the key kinase in the NF-?B pathway, can also regulate the p53 stability by phosphorylating two serines (S362, S366) upon DNA damage response, which leads to p53 degradation through the2-TrCP dependent pathway. This result links the two major signal pathways NF-?B and p53-often antagonistic-the former a cell survival factor and the latter promoting apoptosis. We will generate mice generating a more stable form of p53 and study how it may affect the outcome of tumors. In summary we have proposed an extensive series of experiments in the next 5 years to understand the regulation of NF-?B and more importantly its role in inflammation and disease.
Chronic inflammation is central to many diseases, like cancer, diabetes, Alzheimer's and aging. We propose to study the molecular mechanism of inflammatory processes by studying the regulation of NF-?B a seminal molecule in the induction of inflammation.
|Font-Burgada, Joan; Shalapour, Shabnam; Ramaswamy, Suvasini et al. (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell 162:766-79|
|Menon, Tushar; Firth, Amy L; Scripture-Adams, Deirdre D et al. (2015) Lymphoid regeneration from gene-corrected SCID-X1 subject-derived iPSCs. Cell Stem Cell 16:367-72|
|Wickersham, Ian R; Sullivan, Heather A; Pao, Gerald M et al. (2015) Lentiviral vectors for retrograde delivery of recombinases and transactivators. Cold Spring Harb Protoc 2015:368-74|
|Firth, Amy L; Menon, Tushar; Parker, Gregory S et al. (2015) Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs. Cell Rep 12:1385-90|
|Pao, Gerald M; Zhu, Quan; Perez-Garcia, Carlos G et al. (2014) Role of BRCA1 in brain development. Proc Natl Acad Sci U S A 111:E1240-8|
|Xia, Yifeng; Liu, Yi-Liang; Xie, Yonghua et al. (2014) A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci Transl Med 6:263ra161|
|Xia, Yifeng; Shen, Shen; Verma, Inder M (2014) NF-ÎºB, an active player in human cancers. Cancer Immunol Res 2:823-30|
|Polley, Smarajit; Huang, De-Bin; Hauenstein, Arthur V et al. (2013) A structural basis for IÎºB kinase 2 activation via oligomerization-dependent trans auto-phosphorylation. PLoS Biol 11:e1001581|
|Narasimamurthy, Rajesh; Hatori, Megumi; Nayak, Surendra K et al. (2012) Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc Natl Acad Sci U S A 109:12662-7|
|Liu, Fei; Xia, Yifeng; Parker, Aaron S et al. (2012) IKK biology. Immunol Rev 246:239-53|
Showing the most recent 10 out of 15 publications