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

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $460,962

## Abstract

ABSTRACT
 The mammalian secretory pathway regulates a cell’s extracellular interactions by making most signals
and receptors that moderate communication. Furthermore, it makes cell adhesion molecules and the
extracellular matrix components. Indeed it makes most proteins needed for a cell to interact with its
extracellular environment, which includes ~⅓ of their protein-coding genes in the human genome. The pathway
has hundreds of machinery proteins used for synthesizing and trafficking secreted proteins, but each of these
have their unique role in the process. However, for the ~8000 protein products of the secretory pathway, it
remains unclear what machinery is needed for each one. To further complicate this, each tissue expresses its
own subset of genes for the secretory pathway. Understanding the organization of the pathway and the
interactions between the secretory pathway machinery and secreted protein products is of considerable
importance since many diseases involve changes in the abundance of secreted and/or membrane proteins,
and these are not always accompanied by changes in mRNA. That is, the secretory pathway itself is regulating
changes in hormone secretion, managing ER stress, or amyloid formation. Thus, there is a fundamental need
to understand (1) what the secretory pathway machinery does, (2) which secreted and membrane proteins rely
upon it, (3) how the hundreds of machinery proteins work together, and (4) what regulates their functions. All of
these items require systems-level experiments, tools, and analyses to fully understand. Here we are
developing such resources for the community to answer fundamental questions. In this work, we are mapping
out all of the secretory pathway machinery and detailing their functions. We describe their functions
mathematically, and build computational models to account for their concerted functions, even for individual
tissues and cell types. Furthermore we are developing software and algorithms to help analyze the models and
use them to diagnose the molecular bases underlying secretory disorders. We are further developing and
deploying experimental techniques to more fully identify all of the secretory machinery proteins needed to
facilitate the production of each specific secreted or membrane protein, and will use those techniques to
identify these interactions for liver-secreted proteins. Finally, we are using genomics and systems biology
techniques to unravel the regulatory mechanisms controlling the tissue-specific expression of the secretory
pathway. Through this, valuable resources will be developed and shared with the community to make it easier
to study the secretory pathway as a biomolecular system.

## Key facts

- **NIH application ID:** 10207258
- **Project number:** 2R35GM119850-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nathan Enoch Lewis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,962
- **Award type:** 2
- **Project period:** 2016-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207258

## Citation

> US National Institutes of Health, RePORTER application 10207258, Unraveling the mammalian secretory pathway through systems biology and algorithm development (2R35GM119850-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10207258. Licensed CC0.

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