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Adaptive and maladaptive repair after kidney injury

Award Number: R01DK076077
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2007
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Adaptive and maladaptive repair after kidney injury - Fibrosis is a common histological manifestation of chronic kidney disease (CKD), characterized by epithelial atrophy, accumulation of myofibroblasts, collagen, and immune cells. The degree of fibrosis predicts kidney function decline regardless of disease etiology. While the kidney can fully regenerate and repair following acute kidney injury (AKI), it is believed that a maladaptive injury response plays a key role in fibrosis development. Over the past 15 years, as part of this grant, our lab has made remarkable progress in systematically dissecting adaptive and maladaptive regeneration, and demonstrated the role of Notch signaling in the injury and repair process. During the first decade of this grant, we demonstrated that transient Notch activation in progenitor cells is essential for reparative regeneration. In contrast, during fibrosis, Notch expression remains elevated in tubule cells, hindering terminal differentiation through metabolic reprogramming. Single cell studies have discovered an emergence of new PT cell subpopulation (named differently by various groups), including failed repair, maladaptive, repairing, injured (iPT), and profibrotic PT (pPT) in diseased kidneys. Experiments indicate that iPT/pPT cells secrete various chemokines, such as IL-34, which play a role in attracting macrophages, and their role in kidney fibrosis and disease has been extensively characterized. Our team has shown that iPT/pPT cells secrete CXCL1, attracting basophils and orchestrating fibrosis by inviting Th17 cells. Computational analysis highlighted strong enrichment for NFKB in iPT/pPT cells. Since NFKB is known regulator not only proinflammatory cytokines such as IL34, CXCL1, CCL2, but also key survival genes, activation of NFKB could create a circuit that may explain the emergence of iPT/pPT and the development of fibrosis. Aim 1: We will systematically characterize iPT/pPT cells in mouse and rat kidney disease models, as well as in patient samples. Specifically, we aim to identify iPT/pPT subtypes, conserved, species- and disease-specific markers, and driver transcriptional programs. We will define the spatial iPT/pPT niche and investigate their cell- cell interactions. Aim 2: To understand essential molecular changes underlying the emergence of iPT/pPT, first, we will characterize their emergence using an engineered CRISPR-Cas9 mouse line with simultaneous readout of lineage histories and gene expression profiles at single-cell resolution. We will validate the role of mitochondrial damage and cytokine treatment by studying isolated tubule cells. Aim 3: We will delineate the contribution of NFKB activation to iPT/pPT differentiation, chemokine secretion, survival, and fibrosis development by using mice with genetic deletion of pathway components.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $636,329 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	12/15/2025	NON-COMPETING CONTINUATION	$636,329
														Subtotal = $636,329

Issue Date FY: 2025 ( Subtotal = $566,334 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	12/19/2024	NON-COMPETING CONTINUATION	$566,334
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	11/20/2024	COMPETING CONTINUATION	$39,120
2025	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	11/20/2024	NON-COMPETING CONTINUATION	-$39,120
														Subtotal = $566,334

Issue Date FY: 2024 ( Subtotal = $636,329 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	12/26/2023	COMPETING CONTINUATION	$636,329
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	12/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $636,329

Issue Date FY: 2022 ( Subtotal = $581,079 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	4/7/2022	NON-COMPETING CONTINUATION	$581,079
														Subtotal = $581,079

Issue Date FY: 2021 ( Subtotal = $581,078 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	3/18/2021	NON-COMPETING CONTINUATION	$581,078
														Subtotal = $581,078

Issue Date FY: 2020 ( Subtotal = $578,663 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/8/2020	NON-COMPETING CONTINUATION	$578,663
														Subtotal = $578,663

Issue Date FY: 2019 ( Subtotal = $578,663 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	3/28/2019	NON-COMPETING CONTINUATION	$578,663
														Subtotal = $578,663

Issue Date FY: 2018 ( Subtotal = $578,663 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	4/11/2018	COMPETING CONTINUATION	$578,663
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	10	8/9/2018	COMPETING CONTINUATION	$113,268
2018	2015	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	4/10/2018	NON-COMPETING CONTINUATION	$0
2018	2015	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	9	8/9/2018	NON-COMPETING CONTINUATION	-$113,268
														Subtotal = $578,663

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $348,000 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/30/2015	NON-COMPETING CONTINUATION	$348,000
														Subtotal = $348,000

Issue Date FY: 2014 ( Subtotal = $433,421 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/29/2014	NON-COMPETING CONTINUATION	$433,421
														Subtotal = $433,421

Issue Date FY: 2013 ( Subtotal = $421,242 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	8/7/2013	NON-COMPETING CONTINUATION	$335,821
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	8/13/2013	SUPPLEMENT FOR EXPANSION	$85,421
														Subtotal = $421,242

Issue Date FY: 2012 ( Subtotal = $348,000 )
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/20/2012	COMPETING CONTINUATION	$348,000
2012	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/20/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $348,000

Issue Date FY: 2011 ( Subtotal = $326,857 )
2011	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/11/2011	NON-COMPETING CONTINUATION	$297,143
2011	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/26/2011	NON-COMPETING CONTINUATION	$29,714
														Subtotal = $326,857

Issue Date FY: 2010 ( Subtotal = $330,159 )
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/24/2010	NON-COMPETING CONTINUATION	$330,159
														Subtotal = $330,159

Issue Date FY: 2009 ( Subtotal = $333,494 )
2009	2009	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/3/2009	NON-COMPETING CONTINUATION	$33,349
2009	2009	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/18/2009	NON-COMPETING CONTINUATION	$300,145
														Subtotal = $333,494

Issue Date FY: 2008 ( Subtotal = $333,494 )
2008	2008	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Kidney Diseases, Urology and Hematology Research	000	2	3/5/2008	NON-COMPETING CONTINUATION	$333,494
														Subtotal = $333,494

Issue Date FY: 2007 ( Subtotal = $340,300 )
2007	2007	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Kidney Diseases, Urology and Hematology Research	000	1	2/12/2007	NEW	$340,300
														Subtotal = $340,300

Grand Total All Awards = $7,952,105

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Adaptive and maladaptive repair after kidney injury

Award Number: R01DK076077

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2007

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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