Alcohol-induced liver damage remains a major health issue. From the previous funding cycle, we determined that mice with impaired signaling through the transforming growth factor ? (TGF-?) pathway, that depends on Smad3 and the Smad adaptor ?2 spectrin (?2SP, Sptbn1) phenocopy Beckwith-Wiedemann Syndrome (BWS). Interestingly, BWS is a human stem cell disorder that is associated with severe developmental abnormalities and liver disease characterized by steatosis, chronic hepatitis, inflammation, and neoplasia. TGF-? deficient mice (Sptbn1+/-, Sptbn1+/-Smad3+/-) had altered function of the chromatin organizing protein CTCF (CCCTC-binding factor), a protein that we found also binds Smad3 and ?2SP. These TGF-? mutant mice also had reduced expression of FancD2, encoding a protein involved in DNA repair, and increased expression of genes associated with stem cells, such as ALDH, encoding aldehyde dehydrogenase, and TERT, encoding the catalytic subunit of telomerase. Moreover, the TGF-? mutant mice were deficient in repair of DNA crosslinking damage. The TGF-? mutant mice are highly sensitive to the toxic effects of alcohol, and develop liver cancers. Therefore, we hypothesize that the inflammation and liver injury in the TGF-? deficient mice result from altered impaired CTCF function that together with Smad3 and ?2SP defect, impair expression of key genes involved in DNA repair (FancD2) and stem cell homeostasis, and that these mice will be susceptible to alcohol-induced liver inflammation, injury, and cancer. To explore these hypotheses, we will test mechanisms by which the tripartite complex of CTCF, Smad3 and ?2SP regulates FancD2 expression, stem cell homeostasis in the liver, and the response to alcohol-induced liver injury. To explore roles for FancD2 in stem cell homeostasis, we will investigate the relationship between this TGF-? pathway and FancD2 in liver cells positive for the stem cell marker CD133 (also known as Prom1) from our TGF-? deficient mice (Sptbn1+/-, Sptbn1+/-Smad3+/-), as well as in vivo studies with our mice that have already been engineered to have inducible impairment of the pathway. This application will enable studies that provide new understanding into stem cell-driven responses to alcohol in the liver, which will provide insights into treating various types of not only alcohol-induced liver injury but liver diseases associated with inflammatory responses.
Our goal is elucidate mechanism for imbalances generated from loss of TGF-? signaling, in genetic and environmental factors (including agents such as alcohol), that lead to deregulation of liver inflammation and injury. Our TGF-? deficient mutants of the Smad3 adaptor ?2SP are highly sensitive to alcohol, with dysregulation of Fanconi anemia (FA) member FancD2, loss of function of CTCF (CCCTC-binding factor) (a DNA-binding protein that regulates higher-order chromatin organization), as well as stem cell molecules such as ALDH. This dysregulation from loss of TGF-? signaling contributes to decreased protection from DNA damage, response to injury and disruption of stem cell homeostasis, that we propose to provide a better understanding of in this application.
|Zhao, Ming; Mishra, Lopa; Deng, Chu-Xia (2018) The role of TGF-?/SMAD4 signaling in cancer. Int J Biol Sci 14:111-123|
|Korkut, Anil; Zaidi, Sobia; Kanchi, Rupa S et al. (2018) A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-? Superfamily. Cell Syst 7:422-437.e7|
|Goulding, David R; Nikolova, Viktoriya D; Mishra, Lopa et al. (2018) Inter-?-inhibitor deficiency in the mouse is associated with alterations in anxiety-like behavior, exploration and social approach. Genes Brain Behav :e12505|
|Mohapatra, Shyam S; Batra, Surinder K; Bharadwaj, Srinivas et al. (2018) Precision Medicine for CRC Patients in the Veteran Population: State-of-the-Art, Challenges and Research Directions. Dig Dis Sci 63:1123-1138|
|Chen, Jian; Zaidi, Sobia; Rao, Shuyun et al. (2018) Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-? Pathway. Gastroenterology 154:195-210|
|Lin, Shu-Hong; Raju, Gottumukkala S; Huff, Chad et al. (2018) The somatic mutation landscape of premalignant colorectal adenoma. Gut 67:1299-1305|
|Lai, Keane K Y; Kweon, Soo-Mi; Chi, Feng et al. (2017) Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology 152:1477-1491|
|Rao, Shuyun; Zaidi, Sobia; Banerjee, Jaideep et al. (2017) Transforming growth factor-? in liver cancer stem cells and regeneration. Hepatol Commun 1:477-493|
|Zhou, Xin; Patel, Darshan; Sen, Sabyasachi et al. (2017) Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis. J Vasc Surg 65:1161-1169|
|Gu, Shoujun; Nguyen, Bao-Ngoc; Rao, Shuyun et al. (2017) Alcohol, stem cells and cancer. Genes Cancer 8:695-700|
Showing the most recent 10 out of 38 publications