# Resolving functional aggregates: A new perspective on innate immune control

> **NIH NIH DP1** · BOSTON CHILDREN'S HOSPITAL · 2020 · $1,239,000

## Abstract

Pattern Recognition Receptors (PRRs) in the innate immune system form the first line of defense against a
broad range of pathogens. PRRs and their downstream signaling molecules often form aggregate-like
macromolecular assemblies and that they utilize such assemblies for their immunological functions. These
findings have transformed our understanding of how the innate immune system detects microbial infection and
how it activates the anti-microbial immune response. However, how these “functional aggregates” are
resolved upon their assembly to ensure transient activation of the potentially harmful inflammatory
signal is not known. How do these functional aggregates interact with the cellular protein quality control
(PQC) system, charged with resolving misfolded protein aggregates (e.g. amyloids)? Is there a commonality or
rather a divergence in cellular response to functional vs. dysfunctional misfolded aggregates? The current
application aims to address these questions by exploring the connections between innate immunity and PQC.
This is uncharted territory, with only few relevant studies that address such questions. Our strategy is to utilize
multidisciplinary approaches, from systematic functional screens to biochemical reconstitution and to structural
dissection. The combination of these approaches is sure to generate deep mechanistic understanding of how
functional aggregates in innate immunity are resolved. It will also provide a new paradigm for how the innate
immune system is regulated and how it can be further controlled for therapeutic gains. Furthermore,
considering the emerging view that many proteins form aggregates-like assemblies or granules as part of
normal physiology (e.g. cytosolic RNA granules and nuclear speckles), our findings and strategies have
implications far beyond the innate immune system.
 The current application represents a new direction in my research. Unlike our previous and current work,
which has largely focused on the mechanisms of how microbial infection activates innate immune response,
this application focuses on the mechanisms of how cells turn off the immune signaling once activated. In
particular, I propose to explore the previously unappreciated interface between innate immunity and cellular
PQC, seeking new unifying principles governing both innate immune signaling complexes and misfolded
dysfunctional aggregates. Underlying this application is my general scientific approach of identifying novel
connections between disciplines and pushing the existing boundaries of the fields. While this proposal deals
with highly risky and challenging problems, as one of the pioneering laboratories for the discovery of functional
aggregates in innate immunity, I believe that we are uniquely positioned to open this new area of research.

## Key facts

- **NIH application ID:** 10001442
- **Project number:** 5DP1AI152074-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Sun Hur
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,239,000
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001442

## Citation

> US National Institutes of Health, RePORTER application 10001442, Resolving functional aggregates: A new perspective on innate immune control (5DP1AI152074-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001442. Licensed CC0.

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