Four years of support are requested in this K08 application by a M.D.-Ph.D. who has just complete pediatric rheumatology training. The applicant is strongly committed to an academic career concerned with the laboratory study, at a fundamental level, of clinically important problems of autoimmune disease. The earlier Ph.D. permits shortening of the duration of the training and its focus on technology transfer of a novel and powerful molecular biologic approach to the problem of the pathogenesis of lupus nephritis. The applicant has been recruited to Columbia and is in the process of being appointed as an Assistant Professor of Pediatrics on the tenure track. The overall environment of the institution is excellent and there is a strong commitment to the development of physician-scientists. Her mentor will be Dr. Winchester who is experienced in the clinical investigation of autoimmune disease. Drs. D'Agati and Erlander will be collaborators who assist in the mentoring process, respectively in the interpretation of renal pathology and in the transferring novel aspects of molecular biology technology to the Columbia laboratory. The primary focus of the training will be the development of the proposed research approach and its application to SLE nephritis, but relevant course work, e.g. genomic informatics, is planned. It is proposed to study the direct involvement of autoreactive T-cells and macrophages in the renal injury of SLE as an alternative to the classical paradigm that nephritis results from an Arthus reaction to autoantigen- containing immune complexes. The work will be based on technical developments that permit examination of the nature of the infiltrating cells and the response of the parenchymal cells to this injury at higher levels of histoarchitectural resolution than have previously been employed. Methods to be used include: laser capture microdissection, a technique that permits isolation of glomeruli and single cells from a frozen section with their RNA intact; linear methods of RNA amplification; improvements in TCR repertoire characterization; and cDNA and oligonucleotide microarrays that enable gene expression profiles of thousands of genes to be determined. The work is divided into two principal aims. The first address the clonal nature of the T-cells infiltrating the glomerulus and their possible specificity for autoantigens as a basis of T-cell recruitment.
The second aim addresses the gene expression phenotype of the infiltrating T- cells and monocytes with respect to activation and sublineage as well as evaluating the modulation in gene expression found in the parenchymal cells as a reflection of paracrine-mediated injury.
|Peterson, Karin S; Huang, Jing-Feng; Zhu, Jessica et al. (2004) Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J Clin Invest 113:1722-33|
|Costello, P J; Winchester, R J; Curran, S A et al. (2001) Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions appear antigen driven. J Immunol 166:2878-86|