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Principal Investigator: Alex Yashchenko
Organization: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
Fiscal Year: 2024
Award: $37,439
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease in the
world. It is characterized by large fluid-filled cysts that disrupt kidney function, eventually leading to end stage
kidney disease. Previous literature indicates that kidney resident macrophages (KRM) are cyst-associated in
human clinical samples and are also found in cystic regions of ADPKD mouse models. KRM accelerate ADPKD
as depletion of KRM reduces cystic index and disease progression in mouse models of the disease. Together,
these data suggest that targeting KRM may have a clinical impact in patients. Unfortunately, it is currently not
feasible to give patients macrophage depleting agents for long periods as these compounds lack specificity,
depleting macrophage populations in multiple tissues. This is an important point as macrophages perform critical
functions as part of an organism’s innate immune defense. Additionally, ADPKD progresses slowly and patients
experience gradual cyst growth and loss of kidney function over several decades of life, thereby requiring long-
term intervention. These data highlight that alternative approaches for long-term, kidney-specific resident
macrophage depletion are desperately needed. In this application, I propose to study niche filling as a means to
achieve long term, kidney specific resident macrophage depletion. This will be achieved by determining the
mechanism of KRM niche filling after temporary depletion and through identification of factors, such as Cx3cr1,
that we propose are critical for KRM niche filling. The central hypothesis of this proposal is that following
temporary depletion, the KRM niche is repopulated via the recruitment and differentiation of bone marrow-
derived Ly6chi monocytes and that this process requires Cx3cr1. In Aim 1, I will map out the kinetics and
mechanism of KRM niche after temporary depletion in a mouse model of ADPKD. In Aim 2, I will test if loss of
Cx3cr1 in monocytes is able to delay KRM niche filling and the progression of cystic disease. My long-term goal
is to understand the mechanism of KRM niche filling and translationally apply KRM-centric findings to clinical
cases of ADPKD.
Terms: <ADPKD><Acceleration><Adoptive Transfer><Adult Polycystic Kidney Disease><Affect><Autosomal Dominant Polycystic Kidney><Autosomal Dominant Polycystic Kidney Disease><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Candidate Disease Gene><Candidate Gene><Clinical><Communities><Cyst><Cystic Kidney Diseases><Cystic Renal Diseases><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Development><Disease><Disease Progression><Disorder><Dominant Polycystic Kidney Disease><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Engraftment><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Generalized Growth><Genes><Genetic mutation><Goals><Growth><Hereditary><Histologic><Histologically><Human><Immune><Immunes><Immunofluorescence Microscopy><Immunology><Inherited><Intervention><Intervention Strategies><Kidney><Kidney Diseases><Kidney Urinary System><Kinetics><Life><Ligands><Liquid substance><Literature><LoxP-flanked allele><Macrophage><Maps><Marrow monocyte><Mice><Mice Mammals><Modern Man><Murine><Mus><Mφ><Nature><Nephrology><Nephropathy><Organism><Patients><Persons><Population><Process><Proliferating><Publishing><Receptor Signaling><Renal Disease><Renal function><Role><Sampling><Sequence Alteration><Specificity><Stromal Cells><Symptoms><Testing><Tissue Growth><Tissues><Work><data exchange><data transfer><data transmission><developmental><disease model><disorder model><early adulthood><emerging adult><experience><flow cytophotometry><floxed><floxed allele><fluid><genomic alteration><indexing><interest><interventional strategy><kidney disorder><kidney function><liquid><living system><monocyte><mouse model><murine model><new approaches><novel approaches><novel strategies><novel strategy><ontogeny><pharmacologic><recruit><renal><renal disorder><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role>