With the proposed Mentored Research Scientist Development Award (K01), the applicant will build upon his prior experiences in studying innate immunity to enhance his skills in cell biology, signal transduction and autoimmunity. The laboratory of Dr. Andrew D. Luster at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The proposed study will provide the applicant with the opportunity to study cellular activation and signal transduction pathways elicited by immune complexes in systemic lupus erythemus (SLE) serum. It has been known for many years that lupus patient's blood contains anti-dsDNA antibodies and DNA in complex. These immune complexes have been shown to be potent inducers of cytokine expression, such as IFN-alpha, which may play a part in the disease process. Toil-Like Receptors (TLRs) are pattern-recognition receptors that serve an important function in detecting pathogens and initiating inflammatory responses. Recently, TLR9 has been demonstrated to mediate responsiveness to unmethylated CpG DNA. Moreover, DNA fragments separated from immune complexes isolated from lupus patients was found to contain high frequencies of CpG dinucleotides. We hypothesized and found that TLR9 contributes in mediating responsiveness to the DNA component in immune complexes from lupus serum. To this end, this application has three specific aims: (1) To determine the domains of TLR9 involved in immune complex recognition and signaling. (2) To identify immune complex responsive cell types and determine the chemokine and cytokine gene expression profile in response to lupus serum. (3) To determine the mechanism of immune complex internalization. ? ?
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