1995 |
Widelitz, Randall Bruce |
R55Activity Code Description: Undocumented code - click on the grant title for more information. |
Cell Biology of Dcc @ University of Southern California |
0.958 |
2000 — 2003 |
Widelitz, Randall Bruce |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
B-Catenin Pathway in Regulated and Induced New Growth @ University of Southern California
This proposal explores how the beta-catenin pathway regulates growth control and tissue modeling during embryonic skin formation, with objectives to manage this pathway in cancer. This pathway is frequently altered in malignancies. Normally beta-catenin binds to E-cadherin, a cell adhesion molecule lost in mammary tumors and to APC (adenomatous polyposis coli), a tumor suppressor lost in colon cancer. APC targets beta-catenin for degradation. Wnt signaling or mutations in the pathway block APC from binding beta-catenin and lead to the accumulation of beta-catenin in the nucleus. Here it associates with LEFs/TCFs to control transcription of c-myc, cyclin D1 other cell proliferation regulatory molecules as well as metalloproteinases involved in tissue modeling. When the molecular pathway is intact, growth control is kept in check. Alterations in the pathway lead to loss of growth control, changes in cell morphology and metastasis. A powerful approach to understanding and managing the pathogenesis of the beta-catenin pathway in cancer is to examine how it is regulated and functions in development. Here we take this approach to learn its physiological function in the skin new growth model. The growth of skin appendages is an established model system for the study of rapid new growth. Beta-catenin is expressed in these regions. Preliminary data showed that beta-catenin expression levels are low in apteric and scale producing regions and higher in feather producing regions. Over-expression of beta-catenin induces new feather growth from apteric and scale forming regions and abnormal growth in feather producing regions, suggesting that higher beta-catenin expression levels lead to the formation of more complex structures. Skin sections showed multiple areas of activated epidermal thickening with high cell proliferation activity preceding new feather growth. We hypothesize that the beta-catenin pathway plays pivotal roles in the control of new growth through interactions with Lef-1 and that subsequent transcriptional activation leads to changes at the level of cell proliferation and tissue modeling. We will study the function of beta-catenin, LEFs/TcFs and cadherin in this new growth using retroviral mediated gene delivery of mutated forms, missing domain-specific functions. The morphological and molecular phenotypes will be assayed in the scale - feather new growth assay. We will also study the cellular mechanisms through which this pathway regulates growth control focusing on cell proliferation and migration and tissue modeling. Knowledge gained from these studies will be useful in the diagnosis and treatment of many forms of cancer.
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0.958 |
2006 — 2008 |
Widelitz, Randall Bruce |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Hormone Regulation of Organ Formation @ University of Southern California
[unreadable] DESCRIPTION (provided by applicant): The long term objective is to understand the molecular mechanism of how sex hormones differentially regulate the morphogenetic process of organ formation, so that the same primordia, or stem cells, can be molded into distinct phenotypes, forming the basis of sexual dimorphism. Skin appendages are very responsive to hormonal stimulation which led to sexual dimorphisms. These are frequently observed on the skin surface as changes in the size, shape, color and function of skin appendages. These effects are hormone dependent and region specific as androgen can cause regression of scalp hairs, but stimulate the growth of beards. At times, errors in hormone dependent growth can lead to congenital anomalies and tumors in the prostate, breast or ovary. The normal and abnormal molecular mechanisms of these processes are mostly unknown. Therefore, a good animal model for in vivo and in vitro studies is needed. In mouse hairs, sexual dimorphism is not apparent. We propose to develop a novel model: the growth of tail feathers in roosters and hens, because it is an in vivo physiological process and accessible for analyses. Our previous work suggested that feather growth depends on localized growth zone (LoGZ) activity in the proximal follicle and this activity is regulated by the Wnt/p-catenin pathway. Furthermore we showed that beta-catenin physically associates with the androgen receptor. Here we hypothesize that the differences of male and female tail feathers are due to differences in LoGZ activities and developmental fates as modulated by sex hormones. Aim 1 will characterize localized hormones, receptors, and enzymes involved in hormone metabolism and identify possible molecular and cellular targets mediating these differences. Aim 2 will study the cross talk between sex hormones and growth related pathways and test whether they are mediated by the canonical 3-catenin pathway. We will explore interactions of sex hormone receptors with members of the Wnt/p-catenin pathway and other co- activators and co-repressors that may modulate the differences of organ formation and growth between hormone responsive and non-responsive regions and between male and female feathers. This novel model is likely to yield new understanding to the molecular nature underlying how sex hormones regulate growth control in various organs and tissues. [unreadable] [unreadable] [unreadable]
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0.958 |
2012 — 2016 |
Chuong, Cheng-Ming [⬀] Widelitz, Randall Bruce |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pattern Formation During Skin Organogenesis @ University of Southern California
DESCRIPTION (provided by applicant): The multi-faceted functions of skin are conferred by its unique three dimensional architecture made up of multiple modules interwoven into an integral organ. To function normally, the size, number, ratio and relative positions of each component have to be precisely regulated. Few studies have focused on how the complex pattern of the skin is built. Current management of severe skin injury has achieved the goal of saving patients' lives by growing a flat layer of epidermis and dermis over the wound. Life-saving as it may be, the replaced skin is composed of relatively simple flat epidermis and dermis and does not function in full due to the lack of skin appendages and key functional modules. Toward the long term objectives of regenerative medicine, we aspire to learn fundamental principles of skin organogenesis that we can apply to better wound healing/regeneration and tissue engineering. In the previous funding period, we focused on the morphogenesis of a single appendage. We now want to study the multi-faceted skin as a whole and to reveal the unifying framework of skin morphogenesis at multiple spatio-temporal scales. We propose to study how the key functional modules of skin are built and patterned. Based on our preliminary data, we postulate that the construction of skin structures occurs through a series of tissue interactions, each with distinct patterning behaviors, built layer by layer, module by module, leading to the integration of the skin as a whole. We choose to focus on three components critical to avian skin function: the feathers, muscles that connect feathers for functionality, and pigment that decorates feathers for communication. Each component represents a different category of patterning behavior in a hierarchical framework. We will study how the boundary between appendage primordia and surrounding dermis is consolidated and hypothesize that periodic patterning, the most fundamental process of skin organogenesis, is established via competition and stabilization of cell adhesion / motility. We will study how the dermal muscle network is established and hypothesize that this adaptive patterning is achieved using appendage primordia as anchor points. We will analyze how the final patterns are pleomorphic and how the process is modulated by environment factors. We will study how skin pigment patterns are painted by the regulatory patterning process. We hypothesize that it is achieved through combinatorial regulation of the migration, proliferation, survival, and / or differentiation of melanocyte progenitors. Similar principles may be used in the patterning of other tissue components. Understanding these patterning behaviors will allow us to apply the principles and initiate self-organizing regenerative processes in various skin disease conditions. PUBLIC HEALTH RELEVANCE: Here we study the patterning mechanisms involved in the development of the skin organ. They include periodic patterning to set up periodically arranged appendage primordia, adaptive patterning to add more components onto extant architecture and regulatory patterning to modulate cell migration or differentiation under physiological or pathological conditions. The study should provide new insights into how the different components are integrated to build a complex organ, and will be useful toward the tissue engineering of a fully functional skin.
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0.958 |
2021 |
Chow, Robert Hsiu-Ping (co-PI) [⬀] Chuong, Cheng-Ming (co-PI) [⬀] Widelitz, Randall Bruce |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Channel Activity During Skin Morphogenesis @ University of Southern California
Our long-term objective is to understand the principles that orchestrate skin morphogenesis in development and wound regeneration. The understanding of biochemical signaling is well advanced. Yet, research into the roles of non-neural bioelectricity lags behind, although evidence for a role of bioelectricity in development, regeneration (McLaughlin and Levin 2018 16; Li et al., 2020 5) and wound healing (Zhao et al. 2012 32) is growing. Our research objective is to study the mechanisms underlying the development and regeneration of skin appendages. In two of our recent research papers, we were inspired to see bioelectricity in action in two tissue patterning processes. First, the orientation of elongating feather buds is regulated by synchronization of oscillating calcium channel activities in bud dermal cells, which is controlled by epidermal Shh signaling (Li et al., 2018 11). Second, the skin frequently shows pigment stripes along the body. The size and spacing of longitudinal pigmentation stripes in Japanese quail was recently shown to be controlled autonomously within melanocyte progenitor populations in a gap junction-dependent manner (Inaba et al., 2019 12). At the time these periodic black/yellow stripes form in embryos, the spacing is in millimeters, a large-scale patterning process that cannot be explained by the classical Turing reaction-diffusion mechanism (patterning in micrometer range). The results led us to think hard about how large-scale tissue architecture is built. While localized signaling centers involving morphogens (e.g., WNT, BMP, FGF) were shown to initiate periodic patterning of feather/hair buds, some unidentified mechanism capable of spanning large distances dynamically must work together to transduce the information over the long-distance scale (Inaba and Chuong, 2019 15). Bioelectricity work here provides a clue. Thus, we organized a multi-disciplinary team to analyze the mechanisms on how biochemical and bioelectric signals integrate to achieve the large-scale tissue patterning. We hypothesize, among other possibilities, transient bioelectrical signaling across gap-junction-coupled cell collectives may allow rapid, long-distance signaling with minimal decrement. Electropotential gradients are harnessed to propagate signals rapidly over the long distance (millimeters in milliseconds) to regulate intracellular messengers and pattern the much larger morphogenetic field. The developing avian skin explants provide an excellent model because of the quantifiable distinct patterns, planar topology for easier channel activity visualization, electric current perturbation and optogenetic gene activation ? not easy in the mouse model. Experimentally, we will first gauge the endogenous bioelectric landscape and evaluate the importance of bioelectricity in these two tissue patterning processes (Aim 1A, 2A). Then we will study how ion channels / gap junctions cross-talk with biochemical signals to achieve tissue patterns (Aim 1B, 2B). The work is likely to produce new findings and insights for future applications to use bioelectricity to benefit wound regeneration.
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0.958 |