This proposal details a five-year research career development plan centered on the development of a platform for the targeted delivery of immunosuppressive agents (ISAs) for crescentic glomerulonephritis (CGN) to the kidney-draining lymph node (KLN), which can increase the efficacy and reduce the toxicity of the current standard therapy for this condition. The candidate is an Instructor in the Department of Medicine at Harvard Medical School (HMS) and Associate Physician in the Division of Renal Medicine at Brigham and Women's Hospital (BWH). This proposal details a clear path to independence for the candidate through the guidance of a multi-disciplinary group of scientists with complementary expertise and exemplary records of mentorship: (1) Reza Abdi (Mentor), an NIH-funded transplant nephrologist at BWH who holds 2 R01 grants, (2) David Salant (Advisor), a world-renowned physician-investigator in glomerular disease at Boston University, (3) Ulrich von Andrian (Advisor), a preeminent lymph node immunologist at HMS, and (4) Jeffrey Karp (Advisor), an engineer at HMS and BWH who conducts pioneering research in drug delivery. This guidance will be bolstered by pursuit of coursework and acquisition of laboratory skills that are tailored to the candidate's career goals and crucial for his successful transition to independence as a physician-scientist in the field of renal immunology. The standard treatment for CGN, a rapidly progressive inflammatory condition that can lead to kidney failure within days, involves the use of potent systemic ISAs that can cause severe side effects that may result in death. Therefore, a pressing unmet clinical need exists for targeted immunosuppressive therapy for CGN, but this remains an underexplored field of research. Fibroblastic reticular cells (FRCs) are resident stromal cells of the lymph node (LN) that contribute actively to the propagation of an adaptive immune response. Preliminary data from a first-author study published by the candidate indicates that the activity of FRCs in the KLN is crucial to the propagation of the cell-mediated immune response in a mouse model of CGN known as nephrotoxic serum nephritis (NTN). In addition, the candidate's laboratory has synthesized a MECA79 antibody-conjugated polymeric nanoparticle (MECA79-NP) that localizes specifically to the KLN during NTN. The main objective of this proposal is to determine how the activation of FRCs promotes a pro-inflammatory milieu in the KLN during CGN in order to identify new targets for a novel therapeutic strategy to combat CGN.
The aims of this proposal are to (1) explore the mechanism governing the adoption of a pro-inflammatory phenotype by FRCs in the KLN during CGN, (2) investigate the role of FRCs in the expansion of the lymphatic vasculature within the KLN during CGN, and (3) develop a first-in-class nanotherapeutic agent that delivers ISAs to the KLN to suppress CGN effectively. The results from these studies could assist in solving the urgent clinical need for precision medicine in the treatment of CGN.
The current standard treatment for the severe inflammatory condition affecting the kidney known as crescentic glomerulonephritis involves the use of systemic immunosuppressive agents, which cause toxicity that can result in death. This proposal seeks to understand better how the immune system becomes activated in the kidney-draining lymph node during crescentic glomerulonephritis in mice and to develop a novel treatment platform consisting of a nanoparticle that delivers immunosuppressive agents selectively to the kidney-draining lymph node. We predict that delivering immunosuppressive agents selectively to the kidney-draining lymph node with this nanoparticle will treat crescentic glomerulonephritis more effectively as well as reduce the toxicity caused by conventional systemic therapy, a finding that could provide a springboard for the use of this nanoparticle in future clinical trials involving human patients. !
