# Unraveling the mammalian secretory pathway through systems biology and algorithm development

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $75,840

## Abstract

ABSTRACT
 The mammalian secretory pathway regulates a cell’s extracellular interactions by making most signals
and receptors that moderate communication and most proteins needed for a cell to interact with its
extracellular environment, which includes ~⅓ of their protein-coding genes in the human genome.
Furthermore, it is frequently harnessed by pathogens, including all enveloped viruses to aid in their synthesis.
 To synthesize and transport these thousands of secreted, membrane, and pathogen proteins, the
pathway has hundreds of machinery proteins, each with their unique role in the process. However, the
regulation of this pathway is poorly understood, especially how it is tailored to the needs of each protein it
produces. The parent grant is elucidating these processes by identifying all secretory pathway machinery
proteins and detailing their functions, with a particular focus on liver-secreted proteins, and liver diseases.
Functional genomics and systems biology techniques are deciphering the regulatory mechanisms controlling
the pathway.
 In this supplement, we build upon the parent grant to decipher the regulatory processes that are
hijacked by enveloped viruses, in particular, the Hepatitis C Virus (HCV), to facilitate the rapid synthesis,
folding and post-translational modification of its coat proteins. Furthermore, the virus successfully manipulates
the host cell to produce their proteins at very high levels, requiring extensive use of host cell resources and
machinery. HCV, for example, primarily infects hepatocytes, and is the leading cause of liver disease including
cirrhosis.
 To decipher how HCV regulates the host cell secretory pathway, we will leverage the Biotinylation by
Antibody Recognition (BAR) method to measure protein-protein interactions between the E1E2 HCV coat
protein, expressed and secreted from hepatocytes. Next we will simultaneously measure the protein secretion
rates and the transcriptome for single cells. These data will be used to identify the essential host cell
machinery needed for virus protein synthesis and allow the use of gene regulatory network analyses and
systems biology modeling to identify how these processes are controlled by the virus. An understanding of how
the HCV regulates the host secretory pathway could yield new targets for direct-acting antivirals, or even
inform how to engineer cells that can produce subunit vaccines to avoid viral damage and reduce transmission.

## Key facts

- **NIH application ID:** 10826657
- **Project number:** 3R35GM119850-08S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nathan Enoch Lewis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $75,840
- **Award type:** 3
- **Project period:** 2016-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826657

## Citation

> US National Institutes of Health, RePORTER application 10826657, Unraveling the mammalian secretory pathway through systems biology and algorithm development (3R35GM119850-08S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10826657. Licensed CC0.

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