Tuesday, July 1, 2025 7/1/2025

Targeting dynein-mediated trafficking in diabetic podocytopathy

Award Number: R01DK136563
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: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

Group Awards By:

View Award Description

Targeting dynein-mediated trafficking in diabetic podocytopathy - Project Summary Diabetic nephropathy (DN) is the most prevalent acquired glomerular disease, affecting ~1 in 3 people with diabetes. DN is characterized by a progressive proteinuric podocytopathy leading to 30-50% of the cases of end stage kidney disease in the United States. Limited understanding of the pathogenic mechanism constrains therapy to slowing the progression instead of preventing the pathogenesis of DN. Podocytes maintain the glomerular filtration barrier by forming a molecular sieve called the slit diaphragm (SD). Mistrafficking of SD proteins, which causes their dyshomeostasis is an early event in diabetic podocyte injury. There is a critical need to define the early trafficking mechanisms underlying the diabetes-disturbed proteostasis in podocyte, to identify targets that inform therapies to prevent rather than postpone the progression of DN. Our recent work implicates a unique role of dynein as an energy-responsive motor protein complex that transduces diabetic signals into disturbed trafficking and proteostasis in podocytes. Hyperglycemia can trigger the expression of dynein subunits, apparently via a shared regulation by energy-responsive kinases and transcription factors (TFs). Forceful transient overexpression of these hyperglycemia-responsive dynein subunits recapitulates the features of diabetic podocytopathy. Our goal of this proposal is to dissect the targetable mechanisms of dynein-mediated trafficking disturbance that compromise the function and viability of podocytes, to guide development of therapies to prevent DN. Our central hypothesis is that dynein mediates an energy-responsive trafficking that causes diabetic podocytopathy with dyshomeostasis of proteins important for podocyte function. Furthermore, we posit that this pathology can be attenuated by targeting the metabolism-responsive regulators of dynein expression or activation. The specific aims include: (1) Determine how diabetes enhances dynein expression and activity underlying podocytopathy. By analyzing the posttranslational modifications of the TFs and epigenetic modifications of dynein gene promoters in conjunction with ChIP and reporter gene assays, we will test whether diabetes activates dynein expression via SP/KLF family TFs modified by energy responsive kinases and whether dynein-mediated trafficking can be reversed by targeting the TFs and kinases. (2) Elucidate how dynein-mediated trafficking disturbs podocyte proteostasis in diabetes. Using live cell and pulse chase-based trafficking and degradation assays, we will test whether dynein has a key role in mediating the energy-responsive changes in protein trafficking that disturb proteostasis. (3) Remodel dynein activity to see if it mitigates podocytopathy in diabetic mouse models. Using a mouse model with podocyte-specific overexpression of Dctn1 (a subunit required for dynein activation), we will test whether activating dynein directly causes podocytopathy. Using a transgenic mouse model with a podocyte-specific knockout of Dctn1, we will test whether targeting dynein-driven pathogenesis can attenuate diabetic podocytopathy. A detailed understanding of dynein’s pathogenic role in DN will facilitate the development of new therapies to prevent DN.


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: 2025 ( Subtotal = $412,308 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/24/2025	NON-COMPETING CONTINUATION	$412,308
														Subtotal = $412,308

Issue Date FY: 2024 ( Subtotal = $429,489 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/1/2024	NEW	$429,489
														Subtotal = $429,489

Grand Total All Awards = $841,797

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting dynein-mediated trafficking in diabetic podocytopathy

Award Number: R01DK136563

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: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer