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Defining the molecular landscape of hyperfiltration-mediated glomerular injury using kidney allografts as a model system

Award Number: K23DK125529
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Defining the molecular landscape of hyperfiltration-mediated glomerular injury using kidney allografts as a model system - ABSTRACT: Long-term kidney allograft survival has not improved significantly over the last two decades. Accumulating data supports the hypothesis that progressive glomerular disease drives late kidney allograft failure, with hyper- filtration mediated glomerular injury being a putative driver. In addition, hyperfiltration is implicated in the progres- sion of kidney diseases such as in diabetes and obesity, both of which have reached epidemic proportions. How- ever, the molecular underpinnings of this shared mechanism of kidney disease progression remain unclear and forms the scientific basis of this proposal. My long-term goal is to understand disease mechanisms driving late allograft loss, with a focus on prolonging allograft lifespan. The overall objective of this application is to elucidate the molecular mechanisms by which hyperfiltration initiates and drives the podocyte detachment process in kidney allografts. We will also test whether parallel mechanisms are operating in an independent cohort of hyperfiltering diabetic patients. Towards achieving this objective my central hypothesis is that hyperfiltration leads to a characteristic molec- ular footprint in the glomerulus that drives podocyte stress and accelerated detachment. To identify the underlying molecular mechanism of hyperfiltration, a combination of bulk- and single cell RNA-sequencing technology will be used to identify glomerular cell-specific gene signatures as well as interactions between cells associated with the glomerular basement membrane that are known to drive podocyte detachment. To enable non-invasive mon- itoring of podocyte loss, we will use urine pellet podocyte detachment assays and measure hyperfiltration using filtration fraction studies. We will test the central hypothesis using three specific aims: Aim 1. Define the glomerular transcriptional response to hyperfiltration. Aim 2. Define the glomerular transcriptional profile that drives accelerated podocyte detachment and identify the effect of hyperfiltration on this relationship. Aim 3: Define the relationship of allograft hyperfiltration with podocyte stress and detachment. The research is innovative as it uses human kidney allografts as a model system to focus on hyperfiltration as a common mechanism of kidney disease progression analyzed by state-of-the-art technologies. The proposed research is significant as the identification of shared pathways of disease progression between kidney diseases could lead to the development of novel targeted therapeutic agents and non-invasive monitoring strategies. Ulti- mately, such knowledge will be crucial to slow down kidney disease progression regardless of its etiology.


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 = $0 )
2026	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	10/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $192,217 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/6/2024	NON-COMPETING CONTINUATION	$192,217
														Subtotal = $192,217

Issue Date FY: 2024 ( Subtotal = $192,240 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/12/2023	NON-COMPETING CONTINUATION	$192,240
														Subtotal = $192,240

Issue Date FY: 2023 ( Subtotal = $192,240 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/20/2022	NON-COMPETING CONTINUATION	$192,240
														Subtotal = $192,240

Issue Date FY: 2022 ( Subtotal = $191,915 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/21/2021	NON-COMPETING CONTINUATION	$191,915
														Subtotal = $191,915

Issue Date FY: 2021 ( Subtotal = $193,415 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/28/2021	NEW	$193,415
														Subtotal = $193,415

Grand Total All Awards = $962,027

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Defining the molecular landscape of hyperfiltration-mediated glomerular injury using kidney allografts as a model system

Award Number: K23DK125529

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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