# A generalizable platform to identify cellular mechanisms that enhance secretory efficiency

> **NIH NIH R35** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $415,000

## Abstract

Project Summary / Abstract
The long-term goal of my lab is to better understand cellular mechanisms that regulate secretory granule
maturation, efficient packaging of hormone, and secretion. In doing so, we will identify drug targets that improve
secretory efficiency during disease. Defects in storage, maturation, or secretion of peptide hormones can lead
to several mental and metabolic disorders, including depression, bipolar disorder, and diabetes. Despite the
importance of this widespread secretion mechanism, the cellular signals that regulate secretory granule
maturation remain unclear. Dense core secretory granules (DCSG) are organelles for the intracellular storage
and stimulus-dependent exocytosis in regulated secretory cells. The hallmarks of granule maturation include:
losing the clathrin coat, acidifying lumen, processing of hormone peptide, and formation of a dense core. This is
consistent for many peptide processing cells. In this proposal, we will focus proinsulin processing in β cells and
proopiomelanocortin (POMC) processing in neurons. In both cell types, distinct subpopulations of DCSG exist.
These subpopulations have different protein and lipid content which affects their secretory capacity. For example,
specific signals lead to preferential secretion of subsets of DCSG granules. We have a limited understanding of
how many subpopulations exist and even less is understood regarding their spatial localization.
A key gap in knowledge is understanding how different signaling networks affect maturation and the formation
of distinct DCSG subpopulations. Additionally, DCSG maturation and the locations it occurs within the cell are
still considered a black box. Thus, use of single-cell unbiased imaging approaches, or those with no requirement
for stains or probes, are ideal for capturing DCSG maturation in the context of the entire cell. Over the next 5
years, we will establish a high-throughput, and generalizable quantitative structural cell biology platform. To do
this, we will leverage soft X-ray tomography (SXT) and fluorescence lifetime imaging microscopy (FLIM). SXT
will be used to map cell organization and quantify the molecular packing of secretory granules (or maturation),
which has not been possible with other approaches. We will complement these studies with functional live-cell
imaging, using a FLIM-based pH probe developed in my lab to monitor granule pH (maturation). We will explore
how different signaling pathways influence DCSG maturation and the spatial localization of specific DCSG
subpopulations. For a holistic understanding of how the rest of the cell contributes to maturation, we will quantify
cellular reorganization by analyzing organelle volumes and inter-organelle contacts. We hypothesize that cAMP
signaling and DCSG interactions with the mitochondria enhance secretory efficiency. The proposed work will
validate our pipeline as a generalizable approach for studying DCSG maturation and uncover new mechanistic
insi...

## Key facts

- **NIH application ID:** 10939926
- **Project number:** 1R35GM154893-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Kate L. White
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939926

## Citation

> US National Institutes of Health, RePORTER application 10939926, A generalizable platform to identify cellular mechanisms that enhance secretory efficiency (1R35GM154893-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10939926. Licensed CC0.

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