Teresa L. Wood, Ph.D. - US grants

Adolescent smoking prevalence has continued to climb with 1997 estimates being the highest reported since 1979. The relationship between adolescent smoking and subsequent nicotine dependence in adulthood has been well established. While biological effects of smoking have been studied in adults, the biobehavioral aspects have not been examined in adolescents. In addition gender differences in smoking that have been reported for adolescents address sociobehavioral factors with limited emphasis on biological data which is essential for understanding adolescent nicotine dependence. The need to identify biomarkers of adolescent nicotine dependence is essential to the health of adolescent smokers. The first aim of this one-factor factorial design study is to characterize the biomarkers of smoke constituent exposure and smoking topography parameters in adolescent smokers. Smoke constituent exposure includes carbon monoxide and plasma nicotine increases post-cigarette and baseline cotinine levels. Smoking topography parameters include puff volume and duration, interpuff interval, and inhalation and exhalation duration. In the second aim smoking topography parameters, smoke constituent exposure, and level of nicotine dependence will be compared between adolescent male and female smokers. The third aim will compare smoke constituent exposure, smoking topography parameters and level of nicotine dependence of prepubescent and later teens. The final aim will contrast biological markers of smoke constituent exposure with accepted behavioral measures of nicotine dependence. Characterizing biological and behavioral aspects of smoking in adolescent boys and girls will provide a foundation to address the gap in this important research area. The proposed study represents the first phase of a program of research that includes analyzing differences in smoking behavior of adolescents from multiple ethnic groups, as well as increasing the scientific basis from which to design tailored smoking prevention and cessation interventions by gender and age group.

[unreadable] DESCRIPTION (provided by applicant): A critical question in biology is how stem and progenitor cells integrate multiple signals from their environment to make decisions to proliferate or to exit the cell cycle and differentiate. The oligodendrocyte lineage has been the focus of numerous studies on how specific growth factors including platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2) and insulin-like growth factor-I (IGF-I) regulate the generation of oligodendrocytes. Our previous studies demonstrated that 1) IGF-I is required for maximal stimulation of oligodendrocyte progenitor cells (OPCs) by PDGF and FGF-2, 2) IGF-I and FGF-2 are synergistic in promoting DNA synthesis in OPCs, and 3) IGF-I, in the presence of FGF-2, increases recruitment of OPCs into the cell cycle. The immediate goals of this proposal are to test the hypotheses that 1) IGF-I, FGF-2 and PDGF coordinately regulate cell cycle progression in OPCs by inducing specific molecular components of the cell cycle, and 2) IGF actions through the IGF type I receptor (IGF-IR) are essential for maximal OPC proliferation. To test the first hypothesis, experiments are proposed to determine how PDGF, FGF-2 and IGF-I coordinate to amplify the induction and activation of the cyclin-cyclin-dependent protein kinases that are essential for G1, S and G2 progression in the OPC. To test the second hypothesis, we will investigate the function of endogenous signaling through the IGF-IR in OPCs in vitro and in vivo using ribozyme technologies and transgenic approaches to inhibit IGF-IR expression and activation. The data from these studies will be important to our understanding of cell cycle regulation in the OPC and will be of broader interest to the field of signal integration in progenitor cell proliferation during development. Moreover, the investigations proposed here will provide the basis for understanding the mechanisms by which proliferation of adult oligodendrocyte progenitors could be enhanced to promote repair of demyelinating lesions in central nervous system disorders such as Multiple Sclerosis. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Gordon Research Conferences on Insulin-like Growth Factors in Physiology & Disease are planned for March 2003, March 2005 and March 2007 in Ventura, California. The IGFs, IGF receptors and the IGF binding proteins currently are the focus of intense investigation across numerous fields and have been implicated in several metabolic and disease states including cancer and diabetes. The conference programs will represent the core of important new research in IGF biology and will be designed to foster interactions between investigators interested in mechanisms of IGF regulation and signaling and those interested in the IGFs in cancer, development, physiology, endocrinology and metabolism. [unreadable] [unreadable] The program for 2003 includes opening presentations on the IGFs in development and in cell transformation. Several sessions on the rapidly emerging area of IGFs and cancer will cover epidemiology and basic mechanisms with a focus on breast and prostate cancer. Other sessions include IGF signaling and the similarities/differences with insulin signaling, the role of IGFs in metabolic diseases, the molecular biology of the IGFs and receptors, the actions of the IGFBPs and their proteases, and the function of IGFs in specific tissues including bone and reproductive tissues. The closing session of the conference will focus on the very new, exciting topic of insulin/IGF signaling in the regulation of life-span and aging. Subsequent meetings that are planned for 2005 and 2007 will focus on current developments in IGF signaling and regulation in critical cellular and disease processes. A significant strength of these conferences is that the biology of the IGFs is of interest to investigators across numerous disciplines. The IGF Gordon Research Conference will be a critical mechanism to promote interaction between investigators interested in IGF biology and those interested in carcinogenesis and metabolic disorders. Such interactions will be essential for rapid progress in understanding the diverse functions and regulation of the IGF ligands, receptors and binding proteins an their roles in normal tissue function and in disease. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Glutamate excitotoxicity has been implicated in loss of oligodendrocytes and their progenitors following ischemia and trauma and in demyelinating diseases. In particular, the progenitor stages of the lineage are most susceptible to many types of damage including excess glutamate. Studies both in vitro and in vivo have demonstrated that excess glutamate kills oligodendrocyte progenitors (OPs) via calcium influx through the AMPA/kainate receptors and that blockade of the AMPA/kainate receptors can protect oligodendrocyte progenitors from excess glutamate as well as from hypoxia-ischemia. Until recently, however, little was known about the mechanisms for glutamate-mediated toxicity. Our previous data demonstrated that excess glutamate leads to translocation of the pro-apoptotic Bcl family member Bax to the mitochondria, release of cytochrome c, activation of caspases 9 and 3 and death of oligodendrocyte progenitors. We also found that IGF-I has a unique ability to sustain activation of Akt and provide long-term protection of the oligodendrocyte progenitors from glutamate or trophic factor withdrawal, and that IGF-mediated survival in the presence of glutamate occurs downstream of calcium influx and upstream of Bax translocation and mitochondrial dysfunction. Thus, the goals of this proposal are to test the hypotheses that 1) glutamate toxicity of late OPs requires a Bax-mediated/mitochondrial pathway, which is activated through a calcium-induced cellular cascade, 2) IGF-I blocks Box-mediated mitochondrial dysfunction in OP cells through sustained IGF-IR/Akt signaling, and 3) perinatal H/I results in death of OPs through Box-mediated apoptosis, which can be blocked through activating Akt. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Current hypotheses concerning the underlying biology of tumor formation and progression are that 1) stem and progenitor cells are targets of transforming mutations and, 2) cancer stem cells exist, which have unlimited proliferative potential. Normal stem cells and cancer stem cells both have the ability to self-renew and are thought to utilize similar pathways for self-renewal, proliferation and fate decisions. Thus, the ability to identify stem and progenitor cells in the breast is critical for future investigations of how transforming events in these cells lead to specific types of breast cancers and for understanding the pathways that regulate proliferation of these cells. The identification of stem and progenitor cells in human breast tissue and breast cancers is an active area of current investigation. However, while multiple characteristics of stem/progenitor cells have been described in human breast and mouse mammary tissue, there are no clear cellular markers available to identify specific stem and early progenitor populations in mammary/breast tissue. Nestin is an intermediate filament, which was originally identified as a marker for neuroepithelial stem cells. Recently, nestin expression was identified in the stem/progenitor cells of multiple tissues and has been proposed as a general marker of stem and progenitor cells. We now have preliminary evidence that nestin identifies a small population'of cells in the mouse mammary gland, in a pattern consistent with its expression in stem and progenitor populations. Moreover, we have found that nestin-positive cells are expanded in specific types of Wnt-induced mammary tumors. The goal of this application is to test the hypothesis that nestin expression identifies a population of self-renewing stem/progenitor cells in the normal mammary gland that are expanded in certain mammary tumors. This research will elucidate a new marker for a subset of breast epithelial cells which have the potential to give rise to specific cell types during normal breast development and to specific types of breast tumors. This novel marker may identify a population of undifferentiated breast tumor stem or progenitor cells. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application seeks funding support for the 2013 Mammary Gland Biology Gordon Research Conference (GRC) and Gordon Research Seminar (GRS). The unique contribution and significance of this long-standing conference is that it will bring together developmental biologists, stem cell biologists, lactation physiologists, breast pathologists, endocrinologists, cancer biologists and oncologists to collectively grapple with important issues in mammary biology and breast cancer. The goals for a successful 2013 program are to inspire important insights, energize new scientists and foster creative collaborations that will deepen our understanding of normal breast physiology and accelerate the eradication of breast cancer. The specific aims of the 2013 meeting will be to 1) provide a program of highly qualified, internationally recognized speakers to address current scientific questions and controversies, 2) foster discussion, unfettered dialog and promote collaborations, and 3) contribute to the training and development of young scientists. The 2013 program has been designed to examine exciting and sometimes controversial areas within mammary gland development and carcinogenesis in which rapid advances are occurring. These include 1) the influence of diabetes/obesity on mammary development, lactation physiology and breast cancer, 2) a better understanding of signaling pathways that regulate both normal development and carcinogenesis, 3) emerging controversies in stem/progenitor cell specification and in tumor initiating cells, 4) the epigenetic regulation of breast cell differentiation and breast cancer, an 5) breast cancer invasion and metastasis. These are important issues, and the innovative approach of pairing research into development and cancer within the same thematic sessions will stimulate new and creative thinking. Other unique features of this meeting include: (i) a tradition of sharing unpublished data; (ii) a program that includes substantial time for questions and open discussion, (iii) an environment that supports informal discussions outside of formal presentations; (iii) active participation and training environment for students and post-docs through the Gordon Research Seminar and at the Gordon Research Conference; and (iv) the encouragement of international collaborations and perspectives.