Inflammation has to be constantly restrained to avoid tissue or organ damage. Imbalanced production of proinflammatory cytokine production and interferons underlies a variety of diseases such as autoimmunity and cancer. Protein geranylgeranylation is a post-translational lipid modification that regulates a variety of cellular functions. Loss of protein geranylgeranylation leads to imbalanced cytokine production and inflammatory disease conditions such as that in the autoinflammatory mevalonate kinase deficiency in humans or in mice deficient for key enzymes catalyzing protein geranylgeranylation. We propose to use a mouse model in combination with biochemical approaches and human genetics to elucidate the mechanisms by which protein geranylgeranylation regulates inflammatory processes through maintenance of balanced cytokine production. Knowledge gained from the proposed research will not only benefit MKD patients, but also patients suffering from common inflammatory diseases such as arthritis and atherosclerosis.
We propose to use mouse and human genetics in combination with biochemical approaches and proteomics to study how geranylgeranylation, a class of lipid modification of proteins, regulates innate immune response.
|Akula, Murali K; Shi, Man; Jiang, Zhaozhao et al. (2016) Control of the innate immune response by the mevalonate pathway. Nat Immunol 17:922-9|
|Tzeng, Te-Chen; Schattgen, Stefan; Monks, Brian et al. (2016) A Fluorescent Reporter Mouse for Inflammasome Assembly Demonstrates an Important Role for Cell-Bound and Free ASC Specks during InÂ Vivo Infection. Cell Rep 16:571-82|
|Mallampati, Saradhi; Sun, Baohua; Lu, Yue et al. (2014) Integrated genetic approaches identify the molecular mechanisms of Sox4 in early B-cell development: intricate roles for RAG1/2 and CK1Îµ. Blood 123:4064-76|