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Niemann-Pick C liver-specific proteostasis and pathology

Award Number: K01DK124450
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Niemann-Pick C liver-specific proteostasis and pathology - ABSTRACT Niemann-Pick disease type C is an invariably fatal autosomal recessive neurovisceral lipid storage disease affecting all ages. Approximately 85% of patients have hepatomegaly which can develop into hepatic steatosis, cirrhosis, hepatocellular carcinoma, and liver failure. Liver defects are especially detrimental in patients with neonatal onset, with 10% dying from liver failure by 6 months of age. Although the liver is a significant contributor to disease, the cellular drivers and pathophysiology are incompletely understood. Niemann-Pick C is caused by over 300 loss-of-function point mutations in the late endosomal/lysosomal cholesterol-exporting protein NPC1. We have previously shown that the most common of these mutations, I1061T, is primarily degraded by FAM134B-dependent ER-selective autophagy (ER-phagy), but there is a crucial need to understand how this pathway works for other disease-causing mutations. Furthermore, preliminary data indicates that the brain and liver express two different isoforms of FAM134B with potentially divergent functions. Consequently, there is a need to understand Niemann-Pick C liver proteostasis and pathogenesis. The next step in addressing these needs is to pursue the overall objectives of this application: (i) determine the effectors mediating tissue-specific NPC1 proteostasis and (ii) define the contribution of different cell types to Niemann-Pick C liver pathology. Here we will test our central hypothesis is that cell type-specific pathways regulate NPC1 proteostasis and drive Niemann-Pick C liver pathology. We will test our hypothesis using induced hepatocytes and neurons from isogenic human iPSCs containing a panel of Niemann-Pick C disease-causing mutations. We will leverage biochemical and genetic assays to establish the extent to which NPC1 proteostasis and FAM134B isoform function are tissue-dependent (Aim 1). Additionally, we will take advantage of Npc1 loxP mice to delete Npc1 globally, in Kupffer cells/macrophages, or hepatocytes to study how these cells contribute to liver pathology, function, and inflammation (Aim 2). These studies are expected to identify novel pathways that significantly contribute to manifestations of Niemann-Pick C-related liver disease across many disease-causing mutations. This will set the stage for the future discovery efforts to identify and test new therapeutic strategies which correct both liver and brain. Our rationale for this project is that defining influence of Kupffer cells/macrophages on tissue-specific proteostasis and liver cell types on disease pathology will provide a strong scientific framework to develop new liver targeted Niemann-Pick C therapeutics. In addition, we outline a career development plan to increase liver biology knowledge by leveraging mentorship, technical training, seminars, liver conferences, and R01 grant writing boot camps. The University of Michigan has committed its support and facilities to allow Dr. Schultz to complete the proposed research and participate in their extensive training seminars. Completion of the proposed 5-year research and training plans will prepare Dr. Schultz for an independent research career and assist in securing an R01 from NIDDK.


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 = -$28,333 )
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	12/30/2024	NON-COMPETING CONTINUATION	-$28,333
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	10/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$31,229
2025	2022	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	2	10/8/2024	NON-COMPETING CONTINUATION	-$31,229
														Subtotal = -$28,333

Issue Date FY: 2024 ( Subtotal = $104,137 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/19/2023	NON-COMPETING CONTINUATION	$147,917
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/2/2024	NON-COMPETING CONTINUATION	-$43,780
														Subtotal = $104,137

Issue Date FY: 2023 ( Subtotal = $147,917 )
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$147,917
2023	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $147,917

Issue Date FY: 2022 ( Subtotal = $119,521 )
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	$119,521
														Subtotal = $119,521

Issue Date FY: 2021 ( Subtotal = $121,022 )
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	1/6/2021	NEW	$121,022
														Subtotal = $121,022

Grand Total All Awards = $464,264

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Niemann-Pick C liver-specific proteostasis and pathology

Award Number: K01DK124450

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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