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You searched for +publisher:"University of Alabama – Birmingham" +contributor:("Lopez, Richard<br>"). Showing records 1 – 2 of 2 total matches.

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1. Anderson, Joshua C. Thrombospondin type-1 repeats and their potential role in inhibiting glioblastoma angiogenesis.

Degree: PhD, 2008, University of Alabama – Birmingham

Thrombospondin-1 (TSP-1) is a 420 kilodalton homotrimeric protein; it is one of the first identified anti-angiogenic proteins found to be expressed in some normal tissues. Peptides derived from the type-1 repeat (TSR) domains of full length TSP-1 have been shown to have anti-angiogenic activity, and thus anti-tumor activity in some non-glioma tumor models. I hypothesized that peptides derived from the TSRs of TSP-1, such as ABT-510, could inhibit angiogenesis and thus malignant glioma tumor growth in vivo. I found that ABT-510 inhibited angiogenesis of the human brain microvascular endothelial cell (MvEC) in an in vitro tubulomorphogenesis assay. To determine the mechanism of this inhibition of angiogenesis by ABT-510, I measured the levels of pro-apoptotic signaling molecules. I found that ABT-510 induced caspase-dependent apoptosis of the human brain MvEC propagated as a monolayer, as well as inhibited tubulomorphogenesis in a caspase-dependent manner. Furthermore, ABT-510’s inhibition of tubulomorphogenesis required CD36, a known receptor for TSP-1.To test the role of the tumor microenvironment in this pro-apoptotic signaling I plated the brain MvEC on different substrates and found a differential induction of apoptosis depending on the matrix on which they were plated. This supports the concept that tumor associated MvEC can be targeted preferentially, and is supported by the observation of multiple other investigators that the matrix (basement membrane) of endothelial cells (EC) in tumor vessels is altered. I then tested the effectiveness of ABT-510 as an anti-angiogenic agent in vivo using two orthotopic models of malignant glioma; one a syngeneic mouse tumor model; and one a xenograft human tumor/mouse host model. ABT-510 treatment resulted in a significant decrease in angiogenesis in both tumor models, and a significant decrease in tumor growth. The anti-angiogenic effect of ABT-510 appeared to be through an increase in apoptotic MvEC within the tumor. These data suggest that ABT-510 is an effective anti-angiogenic agent in vitro and in vivo, and should lead to clinical trials of TSP-1 TSR peptides, likely as part of a combination therapy, in the treatment of patients with malignant glioma.

xv, 158 p. : ill., digital, PDF file.

Pathology

Joint Health Sciences

Glioblastoma Angiogenesis Thrombospondin TSR ABT-510

UNRESTRICTED

Advisors/Committee Members: Gladson, Candece L., Lopez, Richard <br>, Nabors III, Louis B. <br>, Ponnazhagan, Selvarangan <br>, Welch, Danny R..

Subjects/Keywords: Angiogenesis Inhibitors  – therapeutic use <; br>; Brain Neoplasms <; br>; Extracellular Matrix  – physiology <; br>; Glioblastoma  – blood supply <; br>; Glioma <; br>; Neovascularization, Pathologic <; br>; Oligopeptides  – therapeutic use

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Anderson, J. C. (2008). Thrombospondin type-1 repeats and their potential role in inhibiting glioblastoma angiogenesis. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,318

Chicago Manual of Style (16th Edition):

Anderson, Joshua C. “Thrombospondin type-1 repeats and their potential role in inhibiting glioblastoma angiogenesis.” 2008. Doctoral Dissertation, University of Alabama – Birmingham. Accessed February 22, 2020. http://contentdm.mhsl.uab.edu/u?/etd,318.

MLA Handbook (7th Edition):

Anderson, Joshua C. “Thrombospondin type-1 repeats and their potential role in inhibiting glioblastoma angiogenesis.” 2008. Web. 22 Feb 2020.

Vancouver:

Anderson JC. Thrombospondin type-1 repeats and their potential role in inhibiting glioblastoma angiogenesis. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2008. [cited 2020 Feb 22]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,318.

Council of Science Editors:

Anderson JC. Thrombospondin type-1 repeats and their potential role in inhibiting glioblastoma angiogenesis. [Doctoral Dissertation]. University of Alabama – Birmingham; 2008. Available from: http://contentdm.mhsl.uab.edu/u?/etd,318

2. Khotskaya, Yekaterina B. Role of syndecan-1 as key regulator of multiple myeloma pathogenesis.

Degree: PhD, 2009, University of Alabama – Birmingham

Syndecan-1 (CD138), a transmembrane heparan sulfate-bearing proteoglycan, is expressed at high levels on most myeloma cells and is shed into the microenvironment. In patients, high levels of serum syndecan-1 are indicative of poor prognosis and elevation of shed syndecan-1 in animal models dramatically enhances tumor growth, angiogenesis and metastasis. Because syndecan-1 is a key regulator of myeloma pathogenesis, we hypothesized that reduction of syndecan-1 levels expressed by the myeloma cells will block their growth and dissemination. Syndecan-1 knockout and knockdown variants of two human myeloma cell lines, CAG and RPMI-8226, were developed using short hairpin RNA (shRNA) technology. In vitro, knock out of syndecan-1 from the myeloma cell surface resulted in a loss of cell viability via initiation of apoptosis. In contrast, syndecan-1 knockdown cells expressing 14-28% normal syndecan-1 levels were phenotypically similar to the control cells and did not reveal significant growth differences when compared to the control cells in vitro. In contrast, when these knockdown cells were injected into severe combined immunodeficient (SCID) mice in vivo, they formed tumors poorly as compared to cells expressing wild-type levels of syndecan-1. Tumor immunohistology revealed that the VEGF levels were dramatically lower in the knockdown tumors as compared to the controls. Moreover, knockdown of syndecan-1 resulted in grossly underdeveloped vasculature in these tumors. Importantly, most syndecan-1 knockdown cells also failed to grow when injected intravenously into SCID mice, suggesting that post-intravasation steps of the metastatic cascade may be syndecan-1 dependent. Few tumors that arose from knockdown cells in animals injected intravenously formed at extra-osseous sites, further implicating syndecan-1 as a critical molecule for homing of myeloma cells to bone. Taken together, these results indicate that syndecan-1 expression is required for robust myeloma tumor development and growth in vivo via regulation of angiogenesis and metastasis, and that therapies aimed at reducing expression of this proteoglycan may benefit myeloma patients.

1 online resource (xi, 114 p. : ill., digital, PDF file)

Pathology

Joint Health Sciences

Multiple myeloma syndecan-1 angiogenesis heparan sulfate proteoglycan metastasis

UNRESTRICTED

Advisors/Committee Members: Sanderson, Ralph D., Lopez, Richard<br>, Welch, Danny R.<br>, Woods, Anne<br>, Zayzafoon, Majd<br>, Zinn, Kurt R..

Subjects/Keywords: Gene Expression Regulation, Neoplastic<; br>; Melanoma  – metabolism<; br>; Neoplasm Proteins  – biosynthesis<; br>; Neovascularization, Pathologic  – metabolism<; br>; Syndecan-1  – biosynthesis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Khotskaya, Y. B. (2009). Role of syndecan-1 as key regulator of multiple myeloma pathogenesis. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,766

Chicago Manual of Style (16th Edition):

Khotskaya, Yekaterina B. “Role of syndecan-1 as key regulator of multiple myeloma pathogenesis.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed February 22, 2020. http://contentdm.mhsl.uab.edu/u?/etd,766.

MLA Handbook (7th Edition):

Khotskaya, Yekaterina B. “Role of syndecan-1 as key regulator of multiple myeloma pathogenesis.” 2009. Web. 22 Feb 2020.

Vancouver:

Khotskaya YB. Role of syndecan-1 as key regulator of multiple myeloma pathogenesis. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2020 Feb 22]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,766.

Council of Science Editors:

Khotskaya YB. Role of syndecan-1 as key regulator of multiple myeloma pathogenesis. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,766

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