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 C? 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.

Public Health Relevance

Asthma continues to be a global public health problem with an increasing prevalence, and current medical therapy is inadequate for controlling symptoms in nearly half of patients with asthma. This proposal will investigate the central role of a protein called gelsolin in controlling smooth muscle relaxation and inflammation in the lung. By targeting the expression and/or function of this protein, we hope to elucidate a novel therapy for asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL143052-02
Application #
9747349
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Tigno, Xenia
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032