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Mechanisms of ER-Protein Quality Control in Podocytes

Award Number: R01DK132786
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: 11/17/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Mechanisms of ER-Protein Quality Control in Podocytes - Mechanisms of ER Protein Quality Control in Podocytes SUMMARY My laboratory has a long-standing interest in protein folding and degradation within the endoplasmic reticulum (ER) by defining the physiological and pathological importance of mammalian ER quality-control machineries in vivo. ER-associated degradation (ERAD) is the principal protein quality-control mechanism responsible for targeting misfolded proteins in the ER for cytosolic proteasomal degradation. The SEL1L-HRD1 protein complex represents the most conserved branch of ERAD. We recently showed that mice with Sel1L deficiency in podocytes develop proteinuria at ~5 weeks of age and die prematurely with a median life span of ~14 weeks for both males and females (Yoshida et al. 2021 J CIin Invest). Electron microscopic analyses revealed foot process effacement and impaired slit diaphragm in the absence of Sel1L. Mechanistically, we showed that SEL1L-HRD1 ERAD in podocytes plays a critical role in the maturation of nascent nephrin in the ER, without affecting podocyte cell number and survival. In our recent work, our preliminary data suggested a possible crosstalk, or likely synergism, between ERAD and another key degradative pathway autophagy in podocytes. We propose to test the overarching hypothesis that the SEL1L-HRD1 ERAD protein complex plays a critical role in podocytes by coordinating the activation of autophagy, which ensures cellular homeostasis and filtration function. This model challenges/expands the current paradigm in ER biology by placing SEL1L-HRD1 ERAD at the center of cellular function in normal physiology and disease pathogenesis. Using various mouse models, we will accomplish the following Aims: (1) Demonstrate the pathophysiological importance of the crosstalk between SEL1L-HRD1 ERAD and autophagy in podocytes; (2) Determine how SEL1L-HRD1 ERAD controls autophagy activity in podocytes; and (3) Delineate the pathological importance and mechanism of ERAD and autophagy in the pathogenesis of nephrin disease mutants involved in nephrotic syndrome. This study will provide unprecedented insights into the crosstalk among key ER quality control machineries in podocytes, and shed new light on the therapeutic potential of targeting ER homeostasis in podocytes. RELEVANCE TO HUMAN HEALTH: Defects in podocytes and in the formation slit diaphragm, a specialized structure involving many transmembrane proteins, underlie nephrotic syndrome, affecting children and adults of all ages. While the ER quality control systems are presumably integrated to maintain ER homeostasis, the crosstalk between quality-control systems has not yet been investigated in vivo. This study will establish the pathophysiological significance of ERAD and the crosstalk between ERAD and autophagy in podocytes in health and diseases.


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 = $367,304 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/28/2024	NON-COMPETING CONTINUATION	$367,304
														Subtotal = $367,304

Issue Date FY: 2024 ( Subtotal = $397,109 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	7/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$123,812
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,819
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	11/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$372,290
2024	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	7/17/2024	NEW	-$123,812
2024	2023	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	1	11/29/2023	NEW	$0
														Subtotal = $397,109

Issue Date FY: 2023 ( Subtotal = $399,569 )
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	1	12/16/2022	NEW	$399,569
														Subtotal = $399,569

Grand Total All Awards = $1,163,982

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Mechanisms of ER-Protein Quality Control in Podocytes

Award Number: R01DK132786

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: 11/17/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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