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

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $387,500

## Abstract

Project Summary / Abstract
Unraveling the mammalian secretory pathway through systems biology data analysis and algorithm
development. The mammalian secretory system is key to organismal development, cell-cell communication,
and all other cellular functions, since the pathway is the biosynthetic route for thousands of secreted
hormones, extracellular matrix modifiers, membrane proteins, and glycans. Its central role also makes it a hub
for disease. Alzheimer's disease is associated with plaques formed from proteins that are misfolded in the
secretory pathway. Cancer cells alter their microenvironment through the secretion of growth factors and
modification of cell surface glycans. Many infectious diseases interact with membrane proteins and glycans
during the infection process. While the secretory pathway has been studied extensively for more than a
century, the complexity of the system has made it difficult to unravel how thousands of chaperonins, enzymes,
transporters, glycans, metabolites, lipids, and RNAs function together to influence health and disease. The
goal of this proposed research program is to develop a detailed knowledge base of the secretory
pathway and to develop algorithms and tools to use the network for data visualization, analysis, and
model simulations, thereby enabling researchers to elucidate how each component influences the
system. We will further to apply these tools with large scale single and dual sgRNA/CRISPR screens in
order to elucidate novel interactions and mechanisms regulating protein secretion. Specifically, (i) the
knowledge base will contain detailed information about all macromolecules involved in the translation, folding,
modification, glycosylation, and secretion of proteins. This further includes metabolism, which fuels the
pathway. The known functions of each pathway member will be detailed, and their interactions will be
described. Since the knowledge base will be organized to enable its use for systems biology analyses, (ii)
visualization tools and analysis algorithms will be developed and deployed to identify how changes in each
component influence the ability to secrete individual proteins or synthesize specific glycans. (iii) We will
leverage the model to integrate large omics data sets we are generating with collaborators (e.g.,
metabolomics, ribosomal profiling, proteomics, and CRISPR-Cas9 activation and loss-of-function screens) to
study regulation of tissue-specific protein secretion. (iv) We will leverage the data to elucidate novel
interactions and functions for poorly characterized members of the secretory pathway. This research program
will provide, for the first time, a well-defined and curated knowledge base for this complex system, and
enable the use of diverse computational systems biology tools to identify the molecular mechanisms
underlying different cell phenotypes stemming from changes in the secretory pathway.

## Key facts

- **NIH application ID:** 9962424
- **Project number:** 5R35GM119850-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nathan Enoch Lewis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2016-07-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962424

## Citation

> US National Institutes of Health, RePORTER application 9962424, Unraveling the mammalian secretory pathway through systems biology and algorithm development (5R35GM119850-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9962424. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*