# Niemann-Pick C liver-specific proteostasis and pathology

> **NIH NIH K01** · UNIVERSITY OF IOWA · 2024 · $104,137

## Abstract

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 prop...

## Key facts

- **NIH application ID:** 10761784
- **Project number:** 5K01DK124450-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Mark Louis Schultz
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $104,137
- **Award type:** 5
- **Project period:** 2021-02-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10761784

## Citation

> US National Institutes of Health, RePORTER application 10761784, Niemann-Pick C liver-specific proteostasis and pathology (5K01DK124450-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10761784. Licensed CC0.

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