Thursday, December 26, 2024 12/26/2024

Novel therapies that target mitochondrial dysfunction for treatment of a1-antitrypsin deficiency liver disease

Award Number: R01DK131215
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY: α1-antitrypsin deficiency (ATD) liver disease is one of the most common genetic causes of liver disease in children and adults. The only currently available treatment is liver transplantation. The pathobiology of the liver disease begins with a point mutation in α1-antitrypsin (AT), one of the most abundant secretory glycoproteins of the liver. The variant, α1-antitrypsin Z (ATZ), is prone to misfolding and that leads to its accumulation within the early part of the secretory pathway of liver cells. Most of the ATZ accumulates in the endoplasmic reticulum (ER) as polymers and aggregates, and we now know that it is this accumulation of polymerogenic, aggregation-prone ATZ that initiates the process of liver damage by a gain-of-toxic function mechanism. Very little is known about the pathobiological steps after accumulation of ATZ that result in liver damage but it is assumed that liver cell function becomes impaired with stereotypical fibrogenic consequences. Marked alterations of mitochondria have been observed in liver cells of human ATD patients and the PiZ mouse model of ATD, leading to speculation that mitochondrial dysfunction is at least part of the final steps in the demise of liver cell function that characterizes severe ATD liver disease. Over the years we have learned that only a sub-group of homozygotes for ATZ develop progressive liver disease and the majority completely escape clinical effects. This observation has led to the recognition that genetic and environmental modifiers play an important role in the pathobiological effects of ATZ. Work led by the Perlmutter laboratory has shown that the intracellular degradation pathway known as autophagy is a key determinant of ATZ accumulation in liver cells and that drugs which enhance the autophagic degradation of ATZ decrease hepatic fibrosis in animal models, including the ATZ nematode and PiZ mouse models. Other recent studies have shown specificity for the molecular pathways involved in autophagy of specific organelles, and the term `ER-phagy' has recently been recognized as at least part of the process by which ATZ is specifically degraded. Furthermore, a very important new study has shown that at least one ER-phagy pathway is regulated by oxidative phosphorylation genes and mitochondrial function. Based on these considerations and new preliminary data described in the proposal, we now believe that mitochondrial impairment is a key part of the pathobiology of ATD liver disease in two ways, impaired liver cell energy metabolism and reduced autophagic response, and, therein, that mitochondrial function is a very appealing target for potential therapeutic interventions. In this grant we propose to investigate the effects of ATZ accumulation on mitochondrial function to better understand the mechanism by which liver is damaged and to investigate whether mitochondrial function can be targeted for therapy. Our overarching goal with these studies is to provide a basis for clinical trials of human ATD liver disease that target mitochondrial dysfunction.


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 = $548,069 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/2/2024	NON-COMPETING CONTINUATION	$548,069
														Subtotal = $548,069

Issue Date FY: 2024 ( Subtotal = $584,605 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/28/2023	NON-COMPETING CONTINUATION	$548,069
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/20/2024	NON-COMPETING CONTINUATION	$36,536
														Subtotal = $584,605

Issue Date FY: 2023 ( Subtotal = $623,637 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/1/2022	NON-COMPETING CONTINUATION	$561,274
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/25/2023	NON-COMPETING CONTINUATION	$62,363
														Subtotal = $623,637

Issue Date FY: 2022 ( Subtotal = $663,075 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/16/2021	NEW	$663,075
														Subtotal = $663,075

Grand Total All Awards = $2,419,386

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Novel therapies that target mitochondrial dysfunction for treatment of a1-antitrypsin deficiency liver disease

Award Number: R01DK131215

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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