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Principal Investigator: HAMID RABB
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $561,996
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary /Abstract
Acute kidney Injury (AKI) associated morbidity and mortality is a major clinical problem that involves multiple
overlapping pathophysiological mechanisms. Recent observations from our team and others demonstrated that
intestinal microbiota modulates AKI outcome, however the underlying mechanism involved in intestinal
microbiota-kidney crosstalk, especially during the recovery phase, remain poorly understood. Our working
hypothesis for this grant application is that gut microbiota induces specific changes in the kidney T cell population
to mediate AKI outcome and recovery. Furthermore, we hypothesize that short chain fatty acids (SCFAs)
produced by certain gut microbiota communicate with kidney tissue via specific smell receptors, such as G
protein coupled receptor 41 (Gpr41), olfactory receptor 78 (Olfr78) and Olfr558 present in the kidney. To test our
hypotheses, we will (AIM 1) immunophenotype kidney immune cells from wild type (WT), antibiotic treated (AB)
and germ free (GF) mice at baseline, during the early phase of AKI, and during recovery of ischemic and cisplatin
induced AKI. We will conduct mechanistic studies using T cell deficient mice, T cell antibody depletion and
adoptive transfer studies targeting select T cells (e.g. CD4, Tregs, CD3+CD4-CD8- double neg) to determine
roles of select T cells on microbiome effects on AKI. Metagenomic and metabolomics with focus on immune
inflammatory pathways will be measured in AKI and recovery for identification of microbial communities and
metabolites. We will also perform colonization studies with specific bacteria, anti-inflammatory stool (from
pregnant mice) and probiotics in AB treated, GF and WT mice. Furthermore, effect of endotoxin released from
leaking gut on renal immune cells population will be investigated in studies using toll like receptor 4 (TLR4)
deficient mice. To study the role of SCFA signaling receptors in intestinal microbiota–kidney crosstalk (AIM 2)
we will induce AKI in Gpr41-/-, Olfr78-/- and Olfr558-/- mice to delineate role of SCFA signaling during AKI
recovery. We will identify immune cell or resident kidney endothelium/epithelial source of SCFA interaction with
Gpr41, Olfr78 and Olfr558 by evaluating kidney and immune cell specific SCFA receptor deficient mice and
performing bone marrow transplants. Additionally, SCFA producing bacteria and exogenous SCFAs will be
administered to Gpr41-/-, Olfr78-/- and Olfr558-/- mice and its effect examined on AKI outcomes. To make our
lab studies more relevant to human AKI, we will (AIM 3) perform metagenomics of pre and post stool samples
and blood metabolomics from patients undergoing cardiac surgery to find gut microbiota differences between
those that develop AKI and those that are protected. We will investigate the effect of human microbiota from
patients that develop AKI in AB treated, GF mice and SCFA receptor deficient mice. Successful completion of
these studies will help understand immunological effects of gut microbiota-kidney crosstalk and potentially novel
treatment options involving SCFAs and targeting intestinal microbiota, for AKI and recovery.
Terms: <Acute Renal Failure with Renal Papillary Necrosis><Adoptive Transfer><Affect><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibodies><Antiinflammatory Effect><Applications Grants><B7-H1><B7H1><Bacteria><Binding><Blood><Blood Reticuloendothelial System><Blood Serum><Body Tissues><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><CD274><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CDDP><Cardiac Surgery><Cardiac Surgery procedures><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinic><Clinical><Communication><Creatinine><Cysplatyna><Data><Dichlorodiammineplatinum><Endothelium><Endotoxins><Epithelium><Evaluation><FFAR3><FFAR3 gene><Feces><Functional Metagenomics><G protein-coupled receptor 41><GI microbiome><GI microbiota><GPR41><Gastrointestinal microbiota><Germ-Free><Grant Proposals><Heart Surgical Procedures><Homolog of Drosophila TOLL><Human><Immune><Immune Cell Activation><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Subtyping><Immunological><Immunologically><Immunologics><Immunology><Immunophenotyping><Inflammation><Inflammatory><Injury><Injury to Kidney><Intracellular Communication and Signaling><Ischemia><KO mice><Kidney><Kidney Diseases><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Knock-out Mice><Knockout Mice><LYT3><Link><LoxP-flanked allele><Marrow Transplantation><Measures><Mediating><Metabolic><Metagenomics><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Nephropathy><Null Mouse><OKT3 antigen><Olfaction><Outcome><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peyrone's Chloride><Peyrone's Salt><Phase><Phenotype><Platinum Diamminodichloride><Population><Probiotics><Process><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Property><Publishing><Receptor Protein><Receptor Signaling><Recovery><Regulatory T-Lymphocyte><Renal Cell><Renal Disease><Renal Grafting><Renal Transplantation><Renal Transplants><Reperfusion Therapy><Research><Role><Serum><Short-Chain Fatty Acids><Signal Transduction><Signal Transduction Systems><Signaling><Smell><Smell Perception><Source><T-Cells><T-Lymphocyte><T3 Antigens><T3 Complex><T3 molecule><T8 Cells><T8 Lymphocytes><TLR4><TLR4 gene><Testing><Therapeutic Studies><Therapy Research><Tissues><Toll Homologue><Translating><Treg><Tubular><Tubular formation><Volatile Fatty Acids><Wild Type Mouse><Work><acute kidney injury><anti-inflammatory effect><bacteria in the gut><biological signal transduction><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><colitis mouse model><colitis murine model><community microbes><digestive tract microbiome><endotoxin receptor><enteric microbial community><enteric microbiome><enteric microbiota><experiment><experimental research><experimental study><experiments><fecal sample><floxed><floxed allele><gastrointestinal microbial flora><gastrointestinal microbiome><gut bacteria><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><heart surgery><hemodynamics><human flora><human microbial communities><human microbiota><human microflora><human-associated microbial communities><human-associated microbiota><immune activation><immunophenotype><improved><injuries><injury and repair><injury recovery><intestinal biome><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><kidney cell><kidney disorder><kidney injury><kidney ischemia><kidney tx><metabolism measurement><metabolomics><metabonomics><microbial><microbial community><microbial consortia><microbial flora><microbiome><microbiota><microflora><mortality><mouse colitis><multispecies consortia><murine colitis><new drug treatments><new drugs><new marker><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel biomarker><novel drug treatments><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><odor perception><olfactory perception><olfactory receptor><pathway><patient oriented outcomes><polymicrobial community><pregnant><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><receptor><recovery after injury><recovery following injury><recovery post injury><regulatory T-cells><renal><renal disorder><renal injury><renal ischemia><repair><repaired><reperfusion><response><sle2><social role><stool><stool sample><stool specimen><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><toll-like receptor 4><tool><wildtype mouse>