2003 — 2006 |
Lin, Fang-Tsyr |
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. |
Lysophosphatidic Acid Signaling in Ovarian Cancer @ University of Alabama At Birmingham
DESCRIPTION (provided by applicant): The overall goal of this proposal is to study the regulation of signaling pathways mediated by lysophosphatidic acid (LPA) and its associated receptors in ovarian cancer cells. LPA acid and its associated receptors, EDG2, EDG4 and EDG7 of the endothelial differentiation gene (EDG) family, have been shown to contribute to ovarian cancer cell proliferation and tumor invasion. Overexpression of EDG4 has been implicated in the progression of ovarian cancer. Thus, these LPA receptors could serve as therapeutic targets in ovarian cancer. In this proposal, we provided the first evidence for the regulation of EDG4 functions by the proapoptotic protein, Siva-1, and the focal adhesion molecule, TRIP6 (Thyroid Receptor Interacting Protein 6). Our long-term goal is to design nove strategies specifically targeting LPA receptors for therapeutic treatment. Three specific aims will be addressed. In Aim 1, a role for Siva-1 in down-regulation of LPA signaling and induction of apoptosis will be determined. Biochemical approaches and yeast genetics wiIl be utilized to determine the functional significance of the interaction between Siva-1 and EDG4. In Aim 2, the role of TRIP6 in LPA-dependent, EDG4-mediated cell migration and mitogenic signaling will be explored by biochemical approaches and immunofluorescence microscopy. In Aim 3, the specificity of Siva-1 and TRIP6 in regulating different LPA receptors will be determined by biochemical approaches. The knowledge obtained from this study will gain insight into the understanding of LPA signaling and regulation in ovarian cancer.
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1 |
2009 — 2010 |
Lin, Fang-Tsyr |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Role of Trip6 in Malignant Glioma Progression @ Baylor College of Medicine
DESCRIPTION (provided by applicant): Malignant glioma is the most common and lethal primary brain tumor. Despite the improvement of imaging technology and surgical removal of the tumors significantly reduces the mortality of malignant glioma, how to enhance the sensitivity to radiation and chemotherapy, and reduce the risk of tumor invasion and metastasis still remains a big challenge. The LIM domain-containing TRIP6 (Thyroid Hormone Receptor-Interacting Protein 6) is a focal adhesion molecule involved in cell motility and transcriptional control. Through the multidomain-mediated protein-protein interactions, TRIP6 binds to several components of focal complexes and promotes ERK activation, Rho signaling and cell migration in a c-Src-dependent manner. In addition, TRIP6 is capable of shuttling to the nucleus to serve as a coactivator of NF-?B, AP-1 and E2F1 in the transcriptional regulation of genes involved in anti-apoptosis and cell growth. In this proposal, we provide novel data showing that inhibition of TRIP6 expression reduces cell migration, enhances chemosensitivity and prolongs G1 phase of the cell cycle in glioblastoma multiforme cells, suggesting a critical role for TRIP6 in malignant glioma progression. As the levels of TRIP6 mRNA and proteins are overexpressed in glioblastoma multiforme, which is correlated to the disease progression, TRIP6 can be a novel therapeutic target for malignant glioma treatment. To investigate if TRIP6 can serve as a molecular marker in GMB progression and determine if we can target TRIP6 to enhance chemosensitivity and reduce the risk of GBM tumor invasion and metastasis, Aim1 will determine the roles of TRIP6 in chemoresistance, cell cycle progression and cell migration and investigate the underlying molecular mechanisms in malignant glioma cells. Aim 2 will study the biological roles of TRIP6 in GBM tumor proliferation, invasion and metastasis using a xenograft animal model and determine if inhibition of TRIP6 expression can enhance chemosensitivity in vivo. The understanding from this study will help to design more effective therapies for this devastatin disease. PUBLIC HEALTH RELEVANCE: The LIM domain-containing TRIP6 is overexpressed in glioblastoma multiforme and plays a critical role in glioma tumor migration, chemoresistance and proliferation. The goal of this project is to understand the molecular mechanisms in cultured glioma cells and in an animal model in order to translate this understanding into more effective therapies for this devastating disease.
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1 |
2017 — 2021 |
Lin, Fang-Tsyr Lin, Weei-Chin [⬀] |
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. |
Novel Therapeutics For Targeting Checkpoint Dysfunction in Cancer @ Baylor College of Medicine
Proper checkpoint activation is necessary to temporarily halt cell cycle progression when cells are in nutrient-deprived conditions or encounter insults. These safeguard mechanisms are universally lost in cancer cells; nevertheless, some causes for the checkpoint perturbation in cancer remain to be investigated. In addition, it remains a challenge to translate our knowledge in this field into practical cancer therapy. The main goal of this project is to develop novel therapeutics aiming at cancer checkpoint perturbation. In this proposal, first we will study how certain hotspot mutations of tumor suppressor p53 actively inhibit the checkpoint response. Second, we will determine whether some mutant p53 directly promotes DNA replication, and if so, by what mechanism(s). Third, we will identify small molecule inhibitors targeting these molecular events. Lastly, we propose a ?synthetic targeted therapy? strategy and leverage our new findings with the existing knowledge for cancer therapy. In our preliminary study, we have identified several lead inhibitors targeting this event. With the aid of one lead inhibitor we have obtained proof-of-concept to support feasibility of the proposed concept. In short, the proposed study will elucidate novel mechanisms of checkpoint perturbation and translate our discoveries into new therapeutics for a broad range of cancers.
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0.901 |