Ettickan Research
My laboratory studies the intracellular signaling regulating the contraction of bladder smooth muscle (BSM) with particular emphasis on JNK2 and NFkB mediated signaling. In these studies, we are investigating 1) the mechanism(s) by which the increased expression of desmin and vimentin enhances the JNK2 phosphorylation and increases the mitochondrial ROS levels in benign prostatic hyperplasia (BPH) induced obstructed BSM and 2) identifying the mechanism(s) by which JNK2 and NFκB induces the BSM contractile dysfunction in high fat diet (HFD) induced obesity. My laboratory also studies the role of epigenetics in radiation therapy (RT) induced cardiopulmonary fibrosis. In this study, we are investigating the role of DNA methylation, histone modification, non-coding RNAs and micro RNAs in RT induced cardiopulmonary fibrosis in lung and breast cancer murine models and human patients.
Research Projects
Molecular mechanisms of contractile dysfunction in obstructive bladder disease
Lower urinary tract dysfunction due to conditions such as benign prostatic hyperplasia (BPH)-induced partial bladder outlet obstruction (PBOO) is strongly associated with bladder smooth muscle (BSM) hypertrophy. The molecular pathogenesis of PBOO induced BSM dysfunction in BPH patients is poorly understood. Others and we have demonstrated that the contractile dysfunction and increased mitochondrial ROS is associated with increased expression of the intermediate filament (IFs) proteins desmin and vimentin in obstructed BSM. Previously, we have generated compelling evidence that JNK2 is a major effector of the BSM contractile dysfunction mediated by increased expression of IFs proteins desmin and vimentin, strongly implicating an IFs/JNK2 dependent mechanism in BSM contractile dysfunction in BPH induced PBOO. We are investigating the mechanism(s) by which the increased expression of desmin and vimentin enhances the JNK2 phosphorylation and increases the mitochondrial ROS levels in BPH induced obstructed BSM.
Immunofluorescence analysis of smooth muscle (SM) specific proteins expression in the bladders of wild type (WT) and JNK2 KO mice. Bladder sections prepared from WT and JNK2 KO mice were stained with anti-SMA or anti-SM22 or SMHC antibody followed by Cy3 (red)- and Alexa Fluor 488 (green) conjugated secondary antibodies. Scale bars = 50 μm. The immunofluorescence analysis revealed an increased expression of SM specific proteins (SMA, SMHC and SM22) in the BSM of JNK2 KO mice compared with WT mice.
Molecular mechanisms of BSM contractile dysfunction in obesity
Obesity is a major risk factor for type 2 diabetics mellitus and is strongly associated with bladder contractile dysfunctions. The mechanisms associated with obesity-induced bladder contractile dysfunction are poorly understood. Previous studies have shown that high fat diet (HFD) and palmitate are known to increase JNK and NFκB activation and induce BSM contractile dysfunction. We are investigating the mechanism(s) by which JNK2 and NFκB induces the BSM contractile dysfunction in HFD induced obesity. Systems biology and functional genomics have become an essential analytical tool and play a significant role in understanding the interaction between genes and their associated pathways at the genome level. We use knockout mouse models and multi-omic approach to identify the JNK2 and NFκB targets and delineate the mechanistic roles of NFkB-JNK2 axes in obesity-induced bladder dysfunction.
Role of epigenetics in radiation therapy induced cardiopulmonary fibrosis
Advanced lung and metastatic breast cancers remain the leading cause of cancer related deaths in US. Thoracic and extra thoracic malignancies often promote pulmonary metastases, and lungs are the second most common site for cancer-induced metastases. Radiation therapy (RT) treatment increases cancer free survival rates, but also causes RT-induced cardiopulmonary toxicity in normal tissue that contributes to non-malignant deaths. RT-induced cardiac and pulmonary fibrosis is a multistep process and are associated with excessive proliferation of cardiac and pulmonary cells and extracellular matrix remodeling which leads to cardiac and pulmonary fibrosis and deterioration of heart and lung function. We are investigating the role of DNA methylation, histone modification, non-coding RNAs and microRNAs in radiation therapy induced cardiopulmonary fibrosis in lung and breast cancer murine models and human patients.