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.
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