# Gelsolin modulation of airway hyperresponsiveness and inflammation

> **NIH NIH K08** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $159,009

## Abstract

Project Summary/Abstract
 There is emerging evidence in the literature that diverse classes of novel ligands for asthma can acutely
relax airway smooth muscle (ASM) despite a transient increase in intracellular calcium concentrations, which
has classically been associated with contraction, not relaxation. Gelsolin is a calcium-activated actin severing
protein that depolymerizes the actin cytoskeleton leading to ASM relaxation. Thus, activation of gelsolin by
transient intracellular calcium increases may be the unifying mechanism that would account for ASM relaxation
by these diverse ligands. In this proposal, we present exciting preliminary data demonstrating that mice
genetically lacking gelsolin exhibit impaired ASM relaxation in vitro, ex vivo and in vivo. In addition to severing
actin, intracellular gelsolin has a binding domain for phosphatidylinositol 4,5 bisphosphate (PIP2), which is the
substrate for phospholipase Cβ synthesis of inositol triphosphate (IP3), the critical regulator of smooth muscle
calcium release and contraction. We will further demonstrate that controlling intracellular gelsolin expression and
activation is a therapeutic strategy for ASM cell relaxation using lentiviral-mediated overexpression of full length
gelsolin and by the introduction of a short gelsolin peptide containing the binding domain for PIP2, which would
selectively impair Gq-mediated increases in intracellular calcium. This proposal also demonstrate gelsolin’s role
in the development of lung inflammation, which is another key pathological characteristic in asthma. We propose
to demonstrate that pulmonary macrophages, in which gelsolin is abundantly expressed, can be a target for
immune modulation in allergic lung inflammation. We will demonstrate that local delivery of a peptide fragment
of gelsolin decreases airway smooth muscle contraction and allergic lung inflammation.
 A mentoring committee composed of successful scientists and physician-scientists will provide scientific
expertise in each aspect of the research plan including ion channel physiology, calcium signaling, Th2 lung
inflammation, lung immunology and macrophage biology. A comprehensive plan of intramural and extramural
coursework and training complemented by additional collaborators with expertise in precision cut lung slices and
magnetic twisting cell cytometry will expand the research training and career development. The research topic
is ideal for a path to independent research in areas of airway smooth muscle pathophysiology and lung immune
cell biology in allergic lung inflammation. Taken as a whole, this K08 proposal outlines a robust pathway to
scientific independence and the foundation of a successful and sustained career as a physician-scientist.

## Key facts

- **NIH application ID:** 10463552
- **Project number:** 5K08HL143052-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Maya Mikami
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $159,009
- **Award type:** 5
- **Project period:** 2018-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463552

## Citation

> US National Institutes of Health, RePORTER application 10463552, Gelsolin modulation of airway hyperresponsiveness and inflammation (5K08HL143052-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10463552. Licensed CC0.

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