This project will define two distinct lineages of inflammatory macrophages, determine their cellular origins, their respective roles in the innate response to kidney injury and subsequent processes of repair, and identify the role of a key determinant that may regulate the phagocytic function of one distinct macrophage lineage. In order to carry out this project the candidate will: 1) Determine the origins and functions of distinct populations of macrophages in the kidney;2) study the expression and function of gpNMB, a molecule expressed selectively by a distinct subpopulation of kidney macrophages that may mediate repair and remodeling. The candidate has experience working on inflammatory macrophages and their role in kidney injury and repair, and has published in this area. Two years ago he moved from Prof Savill's group in the UK to Prof Bonventre's group at Harvard in order to focus more on animal models of tissue repair, with particular relevance to the kidney. Complementing his background in the study of macrophages with the scientific environment in the Bonventre lab has resulted in the candidate's ability to propose novel hypotheses relating to the biology of macrophages in vivo during kidney injury and repair. The candidate now has considerable preliminary data. He will master many of the in vivo techniques in the proposal, including, lineage tracing by bone marrow chimerism, Cre-Lox technology and reproducible modeling of injury and repair in the kidney. In addition the proposed study will enable acquisition of skills in proteomics, laser capture microdissection, retroviral gene expression/silencing and molecular cloning. There are accomplished colleagues in the Bonventre laboratory, and nearby at Harvard Medical School who will assist in these areas of development. Relevance: In common diseases affecting the kidney currently lacking therapies, macrophages contribute to scarring and organ damage. However, the same cell-type is the principal immune cell that orchestrates repair. It is proposed that the reason for this paradox is that there are two distinct types of tissue macrophage. My goal is to define these two types of macrophage so that novel therapies can be developed to target one type over another.
| Fligny, Cecile; Duffield, Jeremy S (2013) Activation of pericytes: recent insights into kidney fibrosis and microvascular rarefaction. Curr Opin Rheumatol 25:78-86 |
| Little, Mark A; Al-Ani, Bahjat; Ren, Shuyu et al. (2012) Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLoS One 7:e28626 |
| Rojas, Andres; Chang, Fan-Chi; Lin, Shuei-Liong et al. (2012) The role played by perivascular cells in kidney interstitial injury. Clin Nephrol 77:400-8 |
| Grgic, Ivica; Duffield, Jeremy S; Humphreys, Benjamin D (2012) The origin of interstitial myofibroblasts in chronic kidney disease. Pediatr Nephrol 27:183-93 |
| Chau, B Nelson; Xin, Cuiyan; Hartner, Jochen et al. (2012) MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 4:121ra18 |
| Nelson, Peter J; Rees, Andrew J; Griffin, Matthew D et al. (2012) The renal mononuclear phagocytic system. J Am Soc Nephrol 23:194-203 |
| Duffield, Jeremy S (2012) Dendritic cells take on more tasks in the liver? Hepatology 55:16-9 |
| Schrimpf, Claudia; Xin, Cuiyan; Campanholle, Gabriella et al. (2012) Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury. J Am Soc Nephrol 23:868-83 |
| Guo, Shunhua; Wietecha, Tomasz A; Hudkins, Kelly L et al. (2011) Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis. Kidney Int 80:946-958 |
| Schrimpf, Claudia; Duffield, Jeremy S (2011) Mechanisms of fibrosis: the role of the pericyte. Curr Opin Nephrol Hypertens 20:297-305 |
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