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Article: MicroRNA Targets for Asthma Therapy.

Ramelli, Sabrina C / Gerthoffer, William T

Advances in experimental medicine and biology

2021 Volume 1303, Page(s) 89–105

Abstract: Asthma is a chronic inflammatory obstructive lung disease that is stratified into endotypes. Th2 high asthma is due to an imbalance of Th1/Th2 signaling leading to abnormally high levels of Th2 cytokines, IL-4, IL-5, and IL-13 and in some cases a ... ...

Abstract	Asthma is a chronic inflammatory obstructive lung disease that is stratified into endotypes. Th2 high asthma is due to an imbalance of Th1/Th2 signaling leading to abnormally high levels of Th2 cytokines, IL-4, IL-5, and IL-13 and in some cases a reduction in type I interferons. Some asthmatics express Th2 low, Th1/Th17 high phenotypes with or without eosinophilia. Most asthmatics with Th2 high phenotype respond to beta-adrenergic agonists, muscarinic antagonists, and inhaled corticosteroids. However, 5-10% of asthmatics are not well controlled by these therapies despite significant advances in lung immunology and the pathogenesis of severe asthma. This problem is being addressed by developing novel classes of anti-inflammatory agents. Numerous studies have established efficacy of targeting pro-inflammatory microRNAs in mouse models of mild/moderate and severe asthma. Current approaches employ microRNA mimics and antagonists designed for use in vivo. Chemically modified oligonucleotides have enhanced stability in blood, increased cell permeability, and optimized target specificity. Delivery to lung tissue limits clinical applications, but it is a tractable problem. Future studies need to define the most effective microRNA targets and effective delivery systems. Successful oligonucleotide drug candidates must have adequate lung cell uptake, high target specificity, and efficacy with tolerable off-target effects.
MeSH term(s)	Animals ; Asthma/drug therapy ; Asthma/genetics ; Cytokines ; Disease Models, Animal ; Mice ; MicroRNAs/genetics ; Pulmonary Disease, Chronic Obstructive ; Th2 Cells
Chemical Substances	Cytokines ; MicroRNAs
Language	English
Publishing date	2021-03-31
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-63046-1_6
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Article: Novel

Cordina, Steve M / Afarian, Shant / Gerthoffer, William T / Martino, Anthony / Wilson, Russell / Naritoku, Dean K

Frontiers in neurology

2020 Volume 11, Page(s) 439

Abstract: Background and Purpose: ...

Abstract	Background and Purpose:
Language	English
Publishing date	2020-06-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2020.00439
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Article ; Online: Mechanisms of vascular smooth muscle cell migration.

Gerthoffer, William T

Circulation research

2007 Volume 100, Issue 5, Page(s) 607–621

Abstract: Smooth muscle cell migration occurs during vascular development, in response to vascular injury, and during atherogenesis. Many proximal signals and signal transduction pathways activated during migration have been identified, as well as components of ... ...

Abstract	Smooth muscle cell migration occurs during vascular development, in response to vascular injury, and during atherogenesis. Many proximal signals and signal transduction pathways activated during migration have been identified, as well as components of the cellular machinery that affect cell movement. In this review, a summary of promigratory and antimigratory molecules belonging to diverse chemical and functional families is presented, along with a summary of key signaling events mediating migration. Extracellular molecules that modulate migration include small biogenic amines, peptide growth factors, cytokines, extracellular matrix components, and drugs used in cardiovascular medicine. Promigratory stimuli activate signal transduction cascades that trigger remodeling of the cytoskeleton, change the adhesiveness of the cell to the matrix, and activate motor proteins. This review focuses on the signaling pathways and effector proteins regulated by promigratory and antimigratory molecules. Prominent pathways include phosphatidylinositol 3-kinases, calcium-dependent protein kinases, Rho-activated protein kinase, p21-activated protein kinases, LIM kinase, and mitogen-activated protein kinases. Important downstream targets include myosin II motors, actin capping and severing proteins, formins, profilin, cofilin, and the actin-related protein-2/3 complex. Actin filament remodeling, focal contact remodeling, and molecular motors are coordinated to cause cells to migrate along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. The result is recruitment of cells to areas where the vessel wall is being remodeled. Vessel wall remodeling can be antagonized by common cardiovascular drugs that act in part by inhibiting vascular smooth muscle cell migration. Several therapeutically important drugs act by inhibiting cell cycle progression, which may reduce the population of migrating cells.
MeSH term(s)	Animals ; Cell Movement/physiology ; Humans ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/physiology ; Myocytes, Smooth Muscle/cytology ; Myocytes, Smooth Muscle/physiology ; Signal Transduction/physiology
Language	English
Publishing date	2007-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/01.RES.0000258492.96097.47
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Article: Migration of airway smooth muscle cells.

Gerthoffer, William T

Proceedings of the American Thoracic Society

2007 Volume 5, Issue 1, Page(s) 97–105

Abstract: Migration of smooth muscle cells is a process fundamental to development of hollow organs, including blood vessels and the airways. Migration is also thought to be part of the response to tissue injury. It has also been suggested to contribute to airways ...

Abstract	Migration of smooth muscle cells is a process fundamental to development of hollow organs, including blood vessels and the airways. Migration is also thought to be part of the response to tissue injury. It has also been suggested to contribute to airways remodeling triggered by chronic inflammation. In both nonmuscle and smooth muscle cells numerous external signaling molecules and internal signal transduction pathways contribute to cell migration. The review includes evidence for the functional significance of airway smooth muscle migration, a summary of promigratory and antimigratory agents, and summaries of important signaling pathways mediating migration. Important signaling pathways and effector proteins described include small G proteins, phosphatidylinositol 3-kinases (PI3-K), Rho activated protein kinase (ROCK), p21-activated protein kinases (PAK), Src family tyrosine kinases, and mitogen-activated protein kinases (MAPK). These signaling modules control multiple critical effector proteins including actin nucleating, capping and severing proteins, myosin motors, and proteins that remodel microtubules. Actin filament remodeling, focal contact remodeling and propulsive force of molecular motors are all coordinated to move cells along gradients of chemical cues, matrix adhesiveness, or matrix stiffness. Airway smooth muscle cell migration can be modulated in vitro by drugs commonly used in pulmonary medicine including beta-adrenergic agonists and corticosteroids. Future studies of airway smooth muscle cell migration may uncover novel targets for drugs aimed at modifying airway remodeling.
MeSH term(s)	Actins/physiology ; Animals ; Cell Movement/drug effects ; Cytoskeleton/physiology ; GTP-Binding Proteins/physiology ; Humans ; Muscle, Smooth/cytology ; Myocytes, Smooth Muscle/physiology ; Protein Kinases/physiology ; Respiratory Physiological Phenomena ; Signal Transduction
Chemical Substances	Actins ; Protein Kinases (EC 2.7.-) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2007-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2132421-9
ISSN	1943-5665 ; 1546-3222
ISSN (online)	1943-5665
ISSN	1546-3222
DOI	10.1513/pats.200704-051VS
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Article: Actin cytoskeletal dynamics in smooth muscle contraction.

Gerthoffer, William T

Canadian journal of physiology and pharmacology

2005 Volume 83, Issue 10, Page(s) 851–856

Abstract: Smooth muscles develop isometric force over a very wide range of cell lengths. The molecular mechanisms of this phenomenon are undefined, but are described as reflecting "mechanical plasticity" of smooth muscle cells. Plasticity is defined here as a ... ...

Abstract	Smooth muscles develop isometric force over a very wide range of cell lengths. The molecular mechanisms of this phenomenon are undefined, but are described as reflecting "mechanical plasticity" of smooth muscle cells. Plasticity is defined here as a persistent change in cell structure or function in response to a change in the environment. Important environmental stimuli that trigger muscle plasticity include chemical (e.g., neurotransmitters, autacoids, and cytokines) and external mechanical signals (e.g., applied stress and strain). Both kinds of signals are probably transduced by ionic and protein kinase signaling cascades to alter gene expression patterns and changes in the cytoskeleton and contractile system. Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of smooth muscles is a major goal in muscle cell biology. Some of the signaling cascades likely to be important include calcium-dependent protein kinases, small GTPases (Rho, Rac, cdc42), Rho kinase, protein kinase C (PKC), Src family tyrosine kinases, mitogen-activated protein (MAP) kinases, and p21 activated protein kinases (PAK). There are many potential targets for these signaling cascades including nuclear processes, metabolic pathways, and structural components of the cytoskeleton. There is growing appreciation of the dynamic nature of the actin cytoskeleton in smooth muscles and the necessity for actin remodeling to occur during contraction. The actin cytoskeleton serves many functions that are probably critical for muscle plasticity including generation and transmission of force vectors, determination of cell shape, and assembly of signal transduction machinery. Evidence is presented showing that actin filaments are dynamic and that actin-associated proteins comprising the contractile element and actin attachment sites are necessary for smooth muscle contraction.
MeSH term(s)	Actins/physiology ; Animals ; Cytoskeleton ; Muscle Contraction ; Muscle, Smooth/physiology ; Signal Transduction/physiology
Chemical Substances	Actins
Language	English
Publishing date	2005-10
Publishing country	Canada
Document type	Journal Article ; Review
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/y05-088
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Article: Signal-transduction pathways that regulate visceral smooth muscle function. III. Coupling of muscarinic receptors to signaling kinases and effector proteins in gastrointestinal smooth muscles.

Gerthoffer, William T

American journal of physiology. Gastrointestinal and liver physiology

2005 Volume 288, Issue 5, Page(s) G849–53

Abstract: Stimulation of muscarinic M3 and M2 receptors on gastrointestinal smooth muscle elicits contraction via activation of G proteins that are coupled to a diverse set of downstream signaling pathways and effector proteins. Many studies suggest a canonical ... ...

Abstract	Stimulation of muscarinic M3 and M2 receptors on gastrointestinal smooth muscle elicits contraction via activation of G proteins that are coupled to a diverse set of downstream signaling pathways and effector proteins. Many studies suggest a canonical excitation-contraction coupling pathway that includes activation of phospholipases, production of inositol 1,4,5-trisphosphate and diacylglycerol, release of calcium from the sarcoplasmic reticulum, activation of L-type calcium channels, and activation of nonselective cation channels. These events lead to elevated intracellular calcium concentration, which activates myosin light chain kinase to phosphorylate and activate myosin II thus causing contraction. In addition, muscarinic receptors are coupled to signaling pathways that modulate the effect of activator calcium. The Rho/Rho kinase pathway inhibits myosin light chain phosphatase, one of the key steps in sensitization of the contractile proteins to calcium. Phosphatidylinositol 3-kinases and Src family tyrosine kinases are also activated by muscarinic agonists. Src family tyrosine kinases regulate L-type calcium and nonselective cation channels. Src activation also leads to activation of ERK and p38 MAPKs. ERK MAPKs phosphorylate caldesmon, an actin filament binding protein. P38 MAPKs activate phospholipases and MAPKAP kinase 2/3, which phosphorylate HSP27. HSP27 may regulate cross-bridge function, actin filament formation, and actin filament attachment to the cell membrane. In addition to the well-known role of M3 muscarinic receptors to regulate myoplasmic calcium levels, the integrated effect of muscarinic activation probably also includes signaling pathways that modulate phospholipases, cyclic nucleotides, contractile protein function, and cytoskeletal protein function.
MeSH term(s)	Animals ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gastrointestinal Tract/enzymology ; Gene Expression ; Humans ; Intracellular Signaling Peptides and Proteins ; Muscle Contraction/physiology ; Muscle, Smooth/enzymology ; Phosphatidylinositol 3-Kinases/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Receptors, Muscarinic/physiology ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/metabolism ; src-Family Kinases/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Receptors, Muscarinic ; MAP-kinase-activated kinase 2 (EC 2.7.1.-) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; src-Family Kinases (EC 2.7.10.2) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2005-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	603840-2
ISSN	1522-1547 ; 0193-1857
ISSN (online)	1522-1547
ISSN	0193-1857
DOI	10.1152/ajpgi.00530.2004
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Article ; Online: Epigenetic targets for novel therapies of lung diseases.

Comer, Brian S / Ba, Mariam / Singer, Cherie A / Gerthoffer, William T

Pharmacology & therapeutics

2015 Volume 147, Page(s) 91–110

Abstract: In spite of substantial advances in defining the immunobiology and function of structural cells in lung diseases there is still insufficient knowledge to develop fundamentally new classes of drugs to treat many lung diseases. For example, there is a ... ...

Abstract	In spite of substantial advances in defining the immunobiology and function of structural cells in lung diseases there is still insufficient knowledge to develop fundamentally new classes of drugs to treat many lung diseases. For example, there is a compelling need for new therapeutic approaches to address severe persistent asthma that is insensitive to inhaled corticosteroids. Although the prevalence of steroid-resistant asthma is 5-10%, severe asthmatics require a disproportionate level of health care spending and constitute a majority of fatal asthma episodes. None of the established drug therapies including long-acting beta agonists or inhaled corticosteroids reverse established airway remodeling. Obstructive airways remodeling in patients with chronic obstructive pulmonary disease (COPD), restrictive remodeling in idiopathic pulmonary fibrosis (IPF) and occlusive vascular remodeling in pulmonary hypertension are similarly unresponsive to current drug therapy. Therefore, drugs are needed to achieve long-acting suppression and reversal of pathological airway and vascular remodeling. Novel drug classes are emerging from advances in epigenetics. Novel mechanisms are emerging by which cells adapt to environmental cues, which include changes in DNA methylation, histone modifications and regulation of transcription and translation by noncoding RNAs. In this review we will summarize current epigenetic approaches being applied to preclinical drug development addressing important therapeutic challenges in lung diseases. These challenges are being addressed by advances in lung delivery of oligonucleotides and small molecules that modify the histone code, DNA methylation patterns and miRNA function.
MeSH term(s)	Animals ; Bronchodilator Agents/administration & dosage ; DNA Methylation/drug effects ; DNA Methylation/genetics ; Drug Delivery Systems/methods ; Drug Delivery Systems/trends ; Epigenesis, Genetic/drug effects ; Epigenesis, Genetic/genetics ; Gene Targeting/methods ; Gene Targeting/trends ; Humans ; Lung Diseases/genetics ; Lung Diseases/therapy
Chemical Substances	Bronchodilator Agents
Language	English
Publishing date	2015-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2014.11.006
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Article ; Online: Emerging targets for novel therapy of asthma.

Gerthoffer, William T / Solway, Julian / Camoretti-Mercado, Blanca

Current opinion in pharmacology

2013 Volume 13, Issue 3, Page(s) 324–330

Abstract: Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors ( ... ...

Abstract	Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors (GPCRs) including bitter taste receptors (TAS2R) agonists and prostaglandin EP4 receptor agonists elicit ASM relaxation. The cAMP/PKA pathway continues to be a promising drug target with the emergence of new PDE inhibitors and a novel PKA target protein, HSP20, which mediates smooth muscle relaxation via actin depolymerization. Smooth muscle relaxation can also be elicited by inhibitors of the RhoA/Rho kinase pathway via inhibition of myosin light chain phosphorylation and actin depolymerization. Targeting epigenetic processes that control chromatin remodeling and RNA-induced gene silencing in airway cells also holds great potential for novel asthma therapy. Further investigation may identify agents that inhibit smooth muscle contraction and/or restrain or reverse obstructive remodeling of the airways.
MeSH term(s)	Animals ; Asthma/drug therapy ; Asthma/metabolism ; Asthma/physiopathology ; HSP20 Heat-Shock Proteins/metabolism ; Histone Deacetylases/metabolism ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Receptors, G-Protein-Coupled/agonists ; Receptors, Prostaglandin E, EP4 Subtype/agonists ; rho-Associated Kinases/metabolism
Chemical Substances	HSP20 Heat-Shock Proteins ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Receptors, G-Protein-Coupled ; Receptors, Prostaglandin E, EP4 Subtype ; TAS2R1 protein, human ; rho-Associated Kinases (EC 2.7.11.1) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2013-04-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2013.04.002
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Article: Emerging targets for novel therapy of asthma

Gerthoffer, William T / Solway, Julian / Camoretti-Mercado, Blanca

Current opinion in pharmacology. 2013 June, v. 13, no. 3

2013

Abstract	Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors (GPCRs) including bitter taste receptors (TAS2R) agonists and prostaglandin EP4 receptor agonists elicit ASM relaxation. The cAMP/PKA pathway continues to be a promising drug target with the emergence of new PDE inhibitors and a novel PKA target protein, HSP20, which mediates smooth muscle relaxation via actin depolymerization. Smooth muscle relaxation can also be elicited by inhibitors of the RhoA/Rho kinase pathway via inhibition of myosin light chain phosphorylation and actin depolymerization. Targeting epigenetic processes that control chromatin remodeling and RNA-induced gene silencing in airway cells also holds great potential for novel asthma therapy. Further investigation may identify agents that inhibit smooth muscle contraction and/or restrain or reverse obstructive remodeling of the airways.
Keywords	actin ; agonists ; asthma ; cAMP-dependent protein kinase ; chromatin ; depolymerization ; drugs ; epigenetics ; gene silencing ; inflammation ; molecular biology ; muscle contraction ; myosin light chains ; phosphorylation ; prostaglandins ; smooth muscle ; taste receptors ; therapeutics
Language	English
Dates of publication	2013-06
Size	p. 324-330.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2013.04.002
Database	NAL-Catalogue (AGRICOLA)

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Article: Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.

Ramelli, Sabrina C / Comer, Brian S / McLendon, Jared M / Sandy, Lydia L / Ferretti, Andrew P / Barrington, Robert / Sparks, Jeff / Matar, Majed / Fewell, Jason / Gerthoffer, William T

Molecular therapy. Nucleic acids

2020 Volume 19, Page(s) 1000–1014

Abstract: To address the problem of poor asthma control due to drug resistance, an antisense oligonucleotide complementary to mmu-miR-145a-5p (antimiR-145) was tested in a house dust mite mouse model of mild/moderate asthma. miR-145 was targeted to reduce ... ...

Abstract	To address the problem of poor asthma control due to drug resistance, an antisense oligonucleotide complementary to mmu-miR-145a-5p (antimiR-145) was tested in a house dust mite mouse model of mild/moderate asthma. miR-145 was targeted to reduce inflammation, regulate epithelial-mesenchymal transitions, and promote differentiation of structural cells. In addition, several chemical variations of a nontargeting oligonucleotide were tested to define sequence-dependent effects of the miRNA antagonist. After intravenous administration, oligonucleotides complexed with a pegylated cationic lipid nanoparticle distributed to most cells in the lung parenchyma but were not present in smooth muscle or the mucosal epithelium of the upper airways. Treatment with antimiR-145 and a nontargeting oligonucleotide both reduced eosinophilia, reduced obstructive airway remodeling, reduced mucosal metaplasia, and reduced CD68 immunoreactivity. Poly(A) RNA-seq verified that antimiR-145 increased levels of many miR-145 target transcripts. Genes upregulated in human asthma and the mouse model of asthma were downregulated by oligonucleotide treatments. However, both oligonucleotides significantly upregulated many genes of interferon signaling pathways. These results establish effective lung delivery and efficacy of locked nucleic acid/DNA oligonucleotides administered intravenously, and suggest that some of the beneficial effects of oligonucleotide therapy of lung inflammation may be due to normalization of interferon response pathways.
Language	English
Publishing date	2020-01-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2019.12.033
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