The prevalence of asthma is increasing sharply, but the underlying mechanisms are not fully understood and the therapeutic modalities remain limited. Asthma is a chronic inflammatory disease of the airway induced by overexpression of proinflammatory genes that are regulated by signal pathways in response to various allergens. [For example, it has been shown that house dust mites (HDM) allergens activate TLR4 signaling in epithelial cells to produce cytokines, including IL-33, which activates interleukin-1 receptor 1 (ST2) signaling in Th2 cells and Th2 target cells to induce asthma phenotypes]. A major regulatory mechanism in these signal pathways and gene activation is Pro-directed phosphorylation (pS/T-P). We have previously found that certain pS/T-P motifs can exist in the two completely distinct cis and trans conformations and also identified a unique prolyl isomerase called Pin1 that accelerates their conversion. Importantly, such Pin1-catalyzed conformational regulation often functions as a new molecular timer to act on multiple pathways to coordinate a given biological process to one direction. Significantly, Pin1 is tightly regulated and its deregulation contributes to disease, including asthma, where Pin1 is activated in the airway of human asthma. However, the role of Pin1 in the development and treatment of asthma is not fully understood. Recently, Hypothesizing a role for Pin1 in TLR signaling, we have shown that TLR7/9 ligation activates Pin1, which then activates IRAK1 in TLR7/9 signaling and type I IFN-mediated innate and adaptive immunity. Our preliminary results showed that IL-33 also activated Pin1, whose knockout fully abolished IRAK1 activation, [NF-?B activation], Th2 cytokine production and asthma-like phenotypes induced by IL-33 [or OVA challenge], and potently inhibited cytokine production induced by HDM or LPS in vitro and/or in mice. We identified [several new Pin1 inhibitors, including one that blocked Pin1 activation and cytokine secretion induced by IL-33 in immune cells]. These results led us to hypothesize that Pin1 regulates [TLR4 and ST2 signal pathways] in multiple cells in asthma and is a new drug target for asthma. This proposal is designed to test this novel hypothesis in collaborations with the asthma research expert Elliot Israel and structural expert Linda Nicholson. First, we will use our Pin1 germline and conditional knockout mice to determine the role of Pin1 in regulating [TLR4 and ST2 signaling] in different cells in asthma. Next, we will elucidate the molecular mechanisms of Pin1 function in asthma by determining how Pin1 is activated [by TLR4 and ST2 signaling], how Pin1 regulates IRAK1 and its targets [in TLR4 and ST2 pathways] using cell and mouse asthma models and human asthma specimens, and how Pin1 activates IRAK1 at the structural level. Finally, we will test our new Pin1 inhibitors in cellular and mouse asthma models, and human asthma samples to evaluate their potential as a new therapy for asthma. These studies would uncover a novel mechanism in asthma development, and also could lead to more effective therapies because Pin1 inhibitors, especially when inhaled, might inhibit multiple targets in different cells in asthma.

Public Health Relevance

We have recently identified a unique enzyme called Pin1 as a major regulator of cell signaling under physiological and pathological conditions. The goal of this proposal is to determine whether Pin1 regulates cell signaling in different cells important for asthma development and to evaluate the potential of the new Pin1 enzymatic inhibitors that we have identified in treating asthma using molecular, cellular and mouse models as well as human asthma specimens. These studies would lead to a better understanding of the basic mechanisms of asthma development and might eventually lead to more effective therapies for asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111430-03
Application #
8686940
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2012-08-15
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$722,206
Indirect Cost
$175,413
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Luo, Man-Li; Gong, Chang; Chen, Chun-Hau et al. (2014) Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res 74:3603-16
Liu, Pengda; Begley, Michael; Michowski, Wojciech et al. (2014) Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 508:541-5
Driver, Jane A; Zhou, Xiao Zhen; Lu, Kun Ping (2014) Regulation of protein conformation by Pin1 offers novel disease mechanisms and therapeutic approaches in Alzheimer's disease. Discov Med 17:93-9