Clinical studies have demonstrated a significant loss of respiratory function with age. This results in reduced quality of life, increased propensity for other diseases, and ineffective aerosol drug delivery for the treatment of obstructive respiratory diseases. However, the cellular and molecular basis for age-dependent loss of respiration has not been established. Airway smooth muscle (ASM) plays a significant role in the regulation of respiration by influencing the bronchial tone due to its mechanical (contraction and relaxation) properties. Herein we propose to establish molecular changes that occur in the ASM due to aging that account for loss of respiratory function in the elderly. Preliminary studies demonstrate diminished contractile and relaxation responses of airways and ASM cells in aged (""""""""Old"""""""") rats compared to """"""""Young"""""""" rats. Additional data suggest aging promotes """"""""phenotype plasticity"""""""" or """"""""switching"""""""" in ASM, a phenomenon observed in certain disease processes in which the smooth muscle contractile phenotype is changed to a proliferative/synthetic phenotype. Expression of myosin heavy chain and smooth muscle a-actin (contractile phenotype marker proteins) is lower in ASM obtained from Old rats compared to Young rats. Furthermore, global gene expression profile analysis in ASM cells revealed decreased expression of myostatin, a member of the TGF-b family, known to inhibit the growth and proliferation of myocytes. Lastly, preliminary data from ASM cells suggest diminished intracellular signaling with age to both contractile and relaxant agents that activate G protein-coupled receptors (GPCRs) on ASM. Based on these studies we hypothesize that ASM undergoes phenotype modulation with age that results in decreased contractile and relaxant responsiveness;a loss of GPCR signaling capacity underlies this loss of responsiveness, mediated in part by a loss of TGF-b pathway activation that occurs with age.
In Specific Aim 1 we propose to establish age-dependent changes in ASM phenotype using rat and human airways and ASM cells by employing novel tools such as myograph, optical magnetic twisting cytometry and traction microscopy.
In Specific Aim 2, we propose to establish the mechanistic basis for a phenotype switch in the ASM that occurs with age by detailing changes in the expression and activity of second messengers, effectors and regulators of GPCR signaling that regulate ASM function.
In Specific Aim 3, we propose studies to characterize the effects of myostatin and TGF- b on airways and ASM phenotype, and determine the capacity of TGF- b signaling to reverse the synthetic/proliferative phenotype associated with age. Collectively, these studies seek to identify age-dependent molecular changes in ASM function that contribute to the age- associated decline in respiratory function in the elderly population. Our findings may help develop tools to improve respiratory functions, and modify diagnostic and treatment regimens for obstructive pulmonary diseases in the elderly.

Public Health Relevance

Respiration declines in the elderly population leading to difficulty in breathing and respiratory failure. Smooth muscle lining the airways is an important structural component that regulates respiration and hence is a target for most anti-asthma medications. Studies proposed in this research work will identify cellular and molecular changes in the airway smooth muscle that account for age-dependent change in respiration. The findings will help establish a mechanistic basis for the age-dependent loss of respiration, and ideally identify strategies to improve respiration and modify diagnostic tools and regimens for treatment of obstructive lung diseases in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG041265-03
Application #
8913573
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Murthy, Mahadev
Project Start
2014-09-15
Project End
2017-05-31
Budget Start
2014-09-15
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Sharma, Pawan; Panebra, Alfredo; Pera, Tonio et al. (2016) Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 310:L365-76
Robinson, Mac B; Deshpande, Deepak A; Chou, Jeffery et al. (2015) IL-6 trans-signaling increases expression of airways disease genes in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 309:L129-38
Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K et al. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527:477-83
Lakkaraju, Sirish Kaushik; Yu, Wenbo; Raman, E Prabhu et al. (2015) Mapping functional group free energy patterns at protein occluded sites: nuclear receptors and G-protein coupled receptors. J Chem Inf Model 55:700-8
Pera, Tonio; Hegde, Akhil; Deshpande, Deepak A et al. (2015) Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function. FASEB J 29:4227-35
Deshpande, Deepak A; Yan, Huandong; Kong, Kok-Choi et al. (2014) Exploiting functional domains of GRK2/3 to alter the competitive balance of pro- and anticontractile signaling in airway smooth muscle. FASEB J 28:956-65
Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C et al. (2014) ?-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent. J Biol Chem 289:23065-74
An, Steven S; Robinett, Kathryn S; Deshpande, Deepak A et al. (2012) Reply to: Activation of BK channels may not be required for bitter tastant-induced bronchodilation. Nat Med 18:650-1
Saxena, H; Deshpande, D A; Tiegs, B C et al. (2012) The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH. Br J Pharmacol 166:981-90
Horvat, Sarah J; Deshpande, Deepak A; Yan, Huandong et al. (2012) A-kinase anchoring proteins regulate compartmentalized cAMP signaling in airway smooth muscle. FASEB J 26:3670-9

Showing the most recent 10 out of 15 publications