Fibrosis is the histological manifestation of chronic kidney disease (CKD). While the kidney can fully regenerate and repair following acute kidney injury (AKI), injury response can also follow a maladapative path in fibrosis resulting in epithelial atrophy, accumulation of myofibroblasts, collagen and inflammatory cells. A key bottleneck to progress in our understanding of regeneration and differentiation has been the limited insight into cell-specific genome wide gene expression changes. A revolution in cellular measurement technology is under way. For the first time, we have the ability to monitor genome-wide gene regulation in thousands of individual cells in a single experiment, using single cell ?omic? studies. Such experiments allow us to discover new cell types and states, trace the origin of cells and identify underlying cell- specific gene expression changes therefore, this method shall enable us to understand reparative and maladaptive regeneration in fibrosis. The primary goal of this proposal is to explore the hypothesis that the Notch pathway plays an important role in the development of chronic kidney disease and kidney fibrosis.

Public Health Relevance

One in ten Americans are affected by chronic kidney disease (CKD). CKD is a gene environmental disease. Critical cell type(s) and pathway(s) responsible for disease development remains unknown limiting CKD understanding and new therapeutics development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076077-12
Application #
9902385
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2006-07-01
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Qiu, Chengxiang; Huang, Shizheng; Park, Jihwan et al. (2018) Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat Med 24:1721-1731
Li, Szu-Yuan; Susztak, Katalin (2018) The Role of Peroxisome Proliferator-Activated Receptor ? Coactivator 1? (PGC-1?) in Kidney Disease. Semin Nephrol 38:121-126
Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763
Beckerman, Pazit; Susztak, Katalin (2018) APOL1: The Balance Imposed by Infection, Selection, and Kidney Disease. Trends Mol Med 24:682-695
Li, Szu-Yuan; Park, Jihwan; Qiu, Chengxiang et al. (2017) Increasing the level of peroxisome proliferator-activated receptor ? coactivator-1? in podocytes results in collapsing glomerulopathy. JCI Insight 2:
Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142
Beckerman, Pazit; Qiu, Chengxiang; Park, Jihwan et al. (2017) Human Kidney Tubule-Specific Gene Expression Based Dissection of Chronic Kidney Disease Traits. EBioMedicine 24:267-276
Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438
Han, Seung Hyeok; Wu, Mei-Yan; Nam, Bo Young et al. (2017) PGC-1? Protects from Notch-Induced Kidney Fibrosis Development. J Am Soc Nephrol 28:3312-3322
Ko, Yi-An; Yi, Huiguang; Qiu, Chengxiang et al. (2017) Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease. Am J Hum Genet 100:940-953

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