Abstracts

Abstract

Translational Approach to the Treatment of COPD

Jeanine D’Armiento

Exposure to tobacco smoke is a major risk factor for chronic obstructive pulmonary disease (COPD) with the ultimate tissue destruction in emphysema resulting from an imbalance in protease/antiprotease activity. Our laboratory has demonstrated that lung parenchymal cells in patients with emphysema express MMP-1 as opposed to smokers without the disease and through /in vitro/ and /in vivo/ studies we demonstrated that cigarette smoke can directly induce MMP production in epithelial cells in a MAP Kinase dependent fashion. Subsequent studies identified a novel cigarette smoke responsive (CSR) element within the promoter region of MMP-1. We further delineated the upstream signaling pathway regulating MMP1 induction by cigarette smoke and identified TLR4 as an important regulator of the induction of MMP1. After the identification of the CSE in MMP-1 we used this knowledge to developed a novel mammalian cell–based assay to screen for inhibitors to the smoke induced MMP1 pathway by transfecting a human cell line (HEK 293T) with a vector containing a luciferase reporter gene under the control of the MMP-1 promoter. Using this novel cell based system we screened an NIH library of compounds and identify novel compounds that exhibited strong activity in our assay. This screening has led to several candidate molecules we are pursuing for the treatment of emphysema. We also screened a plant-based library in our system and were able to identify a new depside, jaboticabin, isolated from the fruit jaboticaba, in our assay. Future studies will elucidate the role of these compounds in treating emphysema.

Molecular Mechanisms of Chromosomal Instability That Leads to Tumorigenesis

Yoshinori Watanabe

Chromosomal instability (CIN) causes aneuploidy, which is a potent driver of tumorigenesis. Although there are several possibilities to explain the causes of CIN, the root cause of CIN is elusive. We found that a wide range of CIN cell lines show common defects in the inner centromere-shugoshin network, which coordinates sister chromatid cohesion and kinetochore-microtubule attachment.

Controlling Mammary Genetic Programs Through Transcription Factor Modules and Epigenetic Regulators

Lothar Hennighausen

The mammary gland is a highly specialized organ producing milk during lactation. Development of mammary tissue can be divided into at least four phases, establishment of the ductal tree during puberty, formation of alveoli during pregnancy, lactation and tissue remodeling upon weaning. While proliferation of ductal epithelium is under the control of ovarian steroid hormones, establishment of alveolar epithelium during pregnancy is induced by prolactin through a set of transcription factors, including STAT5 and ELF5. This lecture will focus on molecular mechanisms underlying the specification, proliferation and differentiation of mammary epithelium. It will cover (1) the role of the transcription factors STAT5 and NFIB in activating specific biological programs and (2) the impact of the histone methyltransferases EZH1 and EZH2 in controlling temporal differentiation and cell specification. The contributions of these key regulators were investigated using mouse genetics and large-scale genomics. Notably, STAT5 and NFIB synergistically control genetic programs during pregnancy and EZH2 modulates epithelial differentiation through operating access of transcription factors to mammary-specific genes. Lastly, the epigenetic regulators EZH1 and EZH2 are redundant actors in the specification of mammary epithelium.