Browsing by Author "Gaut, Joseph P."

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    A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease
    (Nature, 2023-07-19) Canela, Victor Hugo; Bowen, William S.; Ferreira, Ricardo Melo; Syed, Farooq; Lingeman, James E.; Sabo, Angela R.; Barwinska, Daria; Winfree, Seth; Lake, Blue B.; Cheng, Ying-Hua; Gaut, Joseph P.; Ferkowicz, Michael; LaFavers, Kaice A.; Zhang, Kun; Coe, Fredric L.; Worcester, Elaine; Jain, Sanjay; Eadon, Michael T.; Williams, James C., Jr.; El-Achkar, Tarek M.; Urology, School of Medicine
    Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.
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    An atlas of healthy and injured cell states and niches in the human kidney
    (Springer Nature, 2023) Lake, Blue B.; Menon, Rajasree; Winfree, Seth; Hu, Qiwen; Ferreira, Ricardo Melo; Kalhor, Kian; Barwinska, Daria; Otto, Edgar A.; Ferkowicz, Michael; Diep, Dinh; Plongthongkum, Nongluk; Knoten, Amanda; Urata, Sarah; Mariani, Laura H.; Naik, Abhijit S.; Eddy, Sean; Zhang, Bo; Wu, Yan; Salamon, Diane; Williams, James C.; Wang, Xin; Balderrama, Karol S.; Hoover, Paul J.; Murray, Evan; Marshall, Jamie L.; Noel, Teia; Vijayan, Anitha; Hartman, Austin; Chen, Fei; Waikar, Sushrut S.; Rosas, Sylvia E.; Wilson, Francis P.; Palevsky, Paul M.; Kiryluk, Krzysztof; Sedor, John R.; Toto, Robert D.; Parikh, Chirag R.; Kim, Eric H.; Satija, Rahul; Greka, Anna; Macosko, Evan Z.; Kharchenko, Peter V.; Gaut, Joseph P.; Hodgin, Jeffrey B.; KPMP Consortium; Eadon, Michael T.; Dagher, Pierre C.; El-Achkar, Tarek M.; Zhang, Kun; Kretzler, Matthias; Jain, Sanjay; Medicine, School of Medicine
    Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.
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    Rationale and design of the Kidney Precision Medicine Project
    (Elsevier, 2021) de Boer, Ian H.; Alpers, Charles E.; Azeloglu, Evren U.; Balis, Ulysses G. J.; Barasch, Jonathan M.; Barisoni, Laura; Blank, Kristina N.; Bomback, Andrew S.; Brown, Keith; Dagher, Pierre C.; Dighe, Ashveena L.; Eadon, Michael T.; El-Achkar, Tarek M.; Gaut, Joseph P.; Hacohen, Nir; He, Yongqun; Hodgin, Jeffrey B.; Jain, Sanjay; Kellum, John A.; Kiryluk, Krzysztof; Knight, Richard; Laszik, Zoltan G.; Lienczewski, Chrysta; Mariani, Laura H.; McClelland, Robyn L.; Menez, Steven; Moledina, Dennis G.; Mooney, Sean D.; O'Toole, John F.; Palevsky, Paul M.; Parikh, Chirag R.; Poggio, Emilio D.; Rosas, Sylvia E.; Rosengart, Matthew R.; Sarwal, Minnie M.; Schaub, Jennifer A.; Sedor, John R.; Sharma, Kumar; Steck, Becky; Toto, Robert D.; Troyanskaya, Olga G.; Tuttle, Katherine R.; Vazquez, Miguel A.; Waikar, Sushrut S.; Williams, Kayleen; Wilson, Francis Perry; Zhang, Kun; Iyengar, Ravi; Kretzler, Matthias; Himmelfarb, Jonathan; Kidney Precision Medicine Project; Medicine, School of Medicine
    Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.
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    The chromatin landscape of healthy and injured cell types in the human kidney
    (Springer Nature, 2024-01-10) Gisch, Debora L.; Brennan, Michelle; Lake, Blue B.; Basta, Jeannine; Keller, Mark S.; Ferreira, Ricardo Melo; Akilesh, Shreeram; Ghag, Reetika; Lu, Charles; Cheng, Ying-Hua; Collins, Kimberly S.; Parikh, Samir V.; Rovin, Brad H.; Robbins, Lynn; Stout, Lisa; Conklin, Kimberly Y.; Diep, Dinh; Zhang, Bo; Knoten, Amanda; Barwinska, Daria; Asghari, Mahla; Sabo, Angela R.; Ferkowicz, Michael J.; Sutton, Timothy A.; Kelly, Katherine J.; De Boer, Ian H.; Rosas, Sylvia E.; Kiryluk, Krzysztof; Hodgin, Jeffrey B.; Alakwaa, Fadhl; Winfree, Seth; Jefferson, Nichole; Türkmen, Aydın; Gaut, Joseph P.; Gehlenborg, Nils; Phillips, Carrie L.; El-Achkar, Tarek M.; Dagher, Pierre C.; Hato, Takashi; Zhang, Kun; Himmelfarb, Jonathan; Kretzler, Matthias; Mollah, Shamim; Kidney Precision Medicine Project (KPMP); Jain, Sanjay; Rauchman, Michael; Eadon, Michael T.; Medicine, School of Medicine
    There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney's active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.