DESCRIPTION (provided by applicant): Dr. John Lee, an Assistant Professor in Medicine at Weill Cornell Medical College, seeks to achieve an academic career as a patient-oriented researcher in the field of kidney transplantation. His overall goal is to become a translational researcher who will develop biomarkers for the diagnosis and prognostication of kidney transplant related complications with the aim of developing targeted therapies for these complications. His research will focus on characterizing the relationship between the gut microbiome and post-transplant complications in kidney transplant recipients. This application describes a series of planned steps to further his development into an independent physician-scientist over the next five years. The gut microbiota (the community of bacteria in the gut) is increasingly being recognized as having an important role in regulating the immune system and in drug metabolism. Little, however, is known about the changes in the gut microbiome after kidney transplantation or about the gut microbiome's contribution to post-transplantation complications. Through a KL2 Scholars Award, Dr. Lee conducted a pilot study on characterizing the gut microbiota after kidney transplantation and reported the gut microbiota's associations with acute rejection (an immune process that can lead to transplant failure), with tacrolimus dosing requirements (a key immunosuppressive drug used to prevent acute rejection), and with post-transplant diarrhea. Based upon this preliminary data, Dr. Lee proposes the following specific aims in this K23 application: Aim 1: To characterize microbial profiles associated with AR and develop novel diagnostic and prognostic AR biomarkers; Aim 2: To investigate whether gut microbiome profiles predict future tacrolimus dosing requirements; Aim 3: To characterize microbial profiles associated with post-transplant diarrhea. To achieve Aim 1, Dr. Lee will collect and profile stool specimens from kidney transplant recipients at the time of kidney transplant biopsy using 16S rRNA deep sequencing, shotgun metagenomic sequencing, and metabolite profiling. He will determine whether gut microbial profiles distinguish kidney transplant recipients with acute cellular rejection (N=40) from those with graft dysfunction but no AR (N=40) and from those with normal biopsies (N=40). Based upon the results, he will develop a PCR-based fecal assay for the rapid diagnosis of ACR. To achieve Aim 2, Dr. Lee plans to recruit 110 kidney transplant recipients prospectively after transplantation and collect weekly fecal specimens in the first month of transplantation and monthly specimen during post-transplant month 2 and 3. He will profile the post- transplant week 1 fecal specimens and will determine whether post-transplant week 1 fecal Faecalibacterium prausnitzii, other bacterial species, genes, and metabolites are associated with tacrolimus dosing requirements at 1 month post-transplantation and based u...