The Role of Fibroblast Activation Protein (FAP) in CKD Progression - Project Summary/Abstract: This NRSA proposal, tailored to Ms. Hibbard, provides high-quality predoctoral research training and career development centered upon her future goals. The sponsor’s excellent mentoring record, collaborations with leading biomedical researchers, and the outstanding environment at the IUSM and Indiana Center for Musculoskeletal Health (ICMH) will foster the successful completion of this project. Additionally, participation in the Preparing Future Faculty and Professionals program for ethics and grant writing courses, manuscript preparation, departmental seminars and journal clubs, as well as national meetings will enhance Ms. Hibbard’s career development towards becoming a well-rounded, independent investigator. Patients with chronic kidney disease (CKD) develop renal fibrosis, which is a common pathological manifestation of virtually all etiologies of CKD, and one of the major causes of end-stage renal failure. Currently, there are no direct therapies for this manifestation. My preliminary data demonstrate that fibroblast activation protein (FAP) is highly expressed in CKD kidney, and our initial RNAseq datasets support that FAP is associated with altered myofibroblast motility and matrix composition. Thus, our models of the interactions between fibrosis and the effects of FAP on this patient phenotype remain incompletely understood. The primary goal of the present application is to test new hypotheses regarding drivers of CKD fibrosis, including FAP as well as its direct targeting in pre-clinical studies. Although my initial results show increased Fap mRNA and protein in the kidney of mice with CKD, the effects of targeting FAP to reduce renal fibrosis, are unstudied. Thus, the central hypothesis is: FAP increases renal fibrosis onset and progression in CKD through enhancing matrix secretion and cell migration, and CD5/LNP-FAPCAR will target FAP+ activated fibroblasts to reduce pathologic CKD outcomes. In Aim 1, the role of Fap in progression of CKD fibrosis will be tested using FAP-KO mice, and in isolated cell culture studies. Aim 2 will test the translational, pre-clinical rescue of renal fibrosis during CKD using a novel targeted anti-fibrotic therapy and scRNAseq. By performing these studies, Ms. Hibbard will gain new research skills in utilizing state-of-the-art translational mouse models, bioinformatic skills, and CKD treatments. Collectively, this proposal will also provide excellent research, ethics, and written and oral presentation training to Ms. Hibbard, as well as test important disease mechanisms that result in kidney fibrosis, and its potential resolution.
