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Defining the role of lncRNA Neat1 and the nuclear paraspeckle in regulating macrophage innate immune gene expresison

Award Number: F31AI197784
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Defining the role of lncRNA Neat1 and the nuclear paraspeckle in regulating macrophage innate immune gene expresison - PROJECT SUMMARY To ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages need to be exquisitely well-controlled. To mount balanced inflammatory responses, macrophages need to be able to coordinate the transcription and processing of thousands of genes that are synthesized de novo following pathogen sensing. Yet, we have an incomplete understanding of the molecular mechanisms employed by macrophages to properly regulate the timing and amplitude of inflammatory gene expression. Key to organization and compartmentalization of the nucleus are biomolecular condensates. Condensates, which include structures like the nucleolus, Cajal body, and nuclear speckle, are known to concentrate functionally related nucleic acids and proteins. We have become interested in one such biomolecular condensate called the nuclear paraspeckle, which forms on a long lncRNA called Neat1. Studies of model cell types (e.g. HeLa and HEK293T) have shown that paraspeckles can aggregate in response to a variety of cellular stresses (e.g. osmotic stress, hypoxia, sodium arsenite), but how paraspeckle dynamics change in response to more physiological stresses—and how they may help regulate the cell’s response to stress—is not well-understood. My project aims to define the role of the paraspeckle in macrophage activation. Our lab recently discovered that macrophage paraspeckles are dynamically regulated over an early time-course of macrophage activation via lipopolysaccharide (LPS). We also found that in response to LPS treatment, Neat1 KO macrophages fail to properly express a large cohort of proinflammatory cytokines, chemokines, and antimicrobial mediators and consequently, cannot control replication of Salmonella enterica or vesicular stomatitis virus (VSV). I hypothesize that macrophage paraspeckles regulate innate immune gene expression by dynamically sequestering and/or releasing nuclear proteins/RNA binding proteins, thus impacting their concentration/bioavailability for participation in innate immune gene expression. Here, I will investigate how different stimuli impact paraspeckle dynamics in macrophages, how paraspeckle composition changes in response to LPS, and how differential sequestration of nuclear proteins in paraspeckles controls innate immune gene expression. In Aim 1, I will define the dynamics of macrophage paraspeckles in response to various cellular stresses, carrying out a high-throughput screen using macrophage cell lines that express GFP-tagged paraspeckles. In Aim 2, I will apply a cutting-edge biotin proximity labeling approach called O- MAP to compositionally define the paraspeckle over a time course of LPS and follow up on how novel paraspeckle-associated proteins contribute to macrophage antimicrobial responses. Together, these experiments will provide important insights into how cellular stresses are transmitted to the nucleus to control paraspeckle dynamics and how reorganization of proteins in and out of paraspeckles controls innate immune gene expression in macrophages.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	3/27/2026	NEW	$49,538
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	1	4/1/2026	NEW	$576
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Defining the role of lncRNA Neat1 and the nuclear paraspeckle in regulating macrophage innate immune gene expresison

Award Number: F31AI197784

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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