# Cholesterol regulation by the cargo receptor SURF4

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $162,650

## Abstract

PROJECT SUMMARY/ABSTRACT
The regulation of human cholesterol plays a critical role in determining a person’s lifetime risk of cardiovascular
disease. Identification of the genes and proteins that underlie this process has improved our fundamental
understanding of how cardiovascular disease develops, and led to the development of cardiovascular drugs
that have greatly benefited public health. While many key regulators of cholesterol homeostasis have been
identified, the majority of the heritable risk of hypercholesterolemia cannot be explained by currently
recognized variants, suggesting the presence of additional unknown mediators. Recently, breakthroughs in
CRISPR-mediated genome editing and massively parallel sequencing have allowed high-throughput, unbiased
functional testing of the entire human genome. During my postdoctoral research, I developed a genome-scale
CRISPR screen for novel regulators of the extracellular secretion of PCSK9, a process that plays a critical role
in modulating plasma cholesterol levels. This led to my discovery of SURF4 as a cargo receptor that promotes
efficient PCSK9 secretion in vitro. However, the physiologic relevance and mechanistic basis of the interaction
between SURF4 and PCSK9 remains unclear. This proposal builds upon my prior work through the generation
of mice with liver-specific deletion of Surf4 and characterization of the consequences to cholesterol
homeostasis (Aim 1), and by altering the coding sequence of human SURF4 to determine which domains
mediate its interaction with PCSK9 (Aim 2). In addition to elucidating the basic biology of PCSK9 secretion,
these studies will inform the potential of SURF4 as a therapeutic target and serve as proof-of-principle for the
power of CRISPR screening to identify novel regulators of protein secretion. This research will be conducted
under the guidance of a primary mentor who has extensive expertise in protein trafficking, cardiovascular
physiology, and genetics as well as a long track record of mentorship for early career physician-scientists who
have successfully transitioned to scientific independence. This work, along with the mentorship and training
activities described in my proposal, will facilitate my development toward my ultimate goal of becoming an
academic physician-scientist and independent investigator.

## Key facts

- **NIH application ID:** 9987756
- **Project number:** 5K08HL148552-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Brian T Emmer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,650
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987756

## Citation

> US National Institutes of Health, RePORTER application 9987756, Cholesterol regulation by the cargo receptor SURF4 (5K08HL148552-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987756. Licensed CC0.

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