Zugl.: Giessen, Universiẗat, Diss., 2007.

Zugl.: Giessen, Universiẗat, Diss., 2007.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Cell and Developmental Biology." Includes bibliographical references (p. 102-115).

Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2007. / David Harrison, Committee Member ; Ravi Bellamkonda, Committee Member ; Larry McIntire, Committee Member ; Oskar Skrinjar, Committee Member ; W. Robert Taylor, Committee Chair ; Robert Guldberg, Committee Chair.

Endothelial Progenitor Cells (EPCs) are thought to participate in the healing of injured vascular endothelium by incorporating into the defect sites to mediate endothelial recovery. Recently, osteopontin (OPN) was shown to be fundamental in accelerating estrogen-dependent healing of injured blood vessels. Here, we are investigating the effect OPN has on EPC behavior. Late outgrowth human EPCs (LEPCs) were derived from circulating monocytes isolated by leukophoresis, and grown in culture until passage six. L-EPCs were then assayed for adhesion, spreading, chemotaxis, and haptotaxis, as well as resistance to detachment by flow electric cellsubstrate impedance sensing (ECIS). The results of standard and ECIS methods showed both dose and time dependent responses in cell adhesion and spreading. In addition, OPN promoted haptotactic migration of EPCs in Boyden chamber assays. LEPCs seeded onto 10μM OPN substrates and exposed to laminar flow had grater survival and higher resistance to detachment than OPN/static and flow only conditions. CD44 and !1 integrins were only responsible for approximately 50% of LEPCs adhesion to OPN compared to the unblocked condition. Western blots showed that Rho GTPases were activated in L-EPCs seeded on OPN. However, this activation could not be completely blocked by either CD44 or !1 integrin antagonists. These data confirm the direct effects of OPN on EPCs adhesion, and suggest that OPN works by mediating cell adhesion during vascular injury.

Heart failure represents amajor cause ofmorbidity andmortality in Western society. Cardiacmyocyte loss due to apoptosis plays a significant role in the progression of heart failure. The extracellularmatrix (ECM) maintains the structural integrity of the heart and allows the transmission of electrical and mechanical signals during cardiac contraction and relaxation. Matricellular proteins, a class of non-structural ECM proteins, play a significant role in ECM homeostasis and intracellular signaling via their interactions with cell surface receptors, structural proteins, and/or soluble extracellular factors such as growth factors and cytokines. Osteopontin (OPN), also called cytokine Eta-1, is a member of the matricellular protein family. The normal heart expresses low levels of OPN. However, OPN expression increases markedly under a variety of pathophysiological conditions of the heart. Many human and transgenic mouse studies provide evidence that increased OPN expression, specifically in myocytes, is associated with increased myocyte apoptosis and myocardial dysfunction. This review summarizes OPN expression in the heart, and its role in myocyte apoptosis and myocardial function.

付記する学位プログラム名: 霊長類学・ワイルドライフサイエンス・リーディング大学院 / 京都大学 / 新制・課程博士 / 博士(医学) / 甲第24837号 / 医博第5005号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤, 能永, 教授 生田, 宏一, 教授 上野, 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Skeletal development is a tightly regulated homeostatic process that requires proper functioning of osteoblasts, the bone forming cells, and osteoclasts, the bone resorbing cells. Improper functioning of either of these cell types results in diseases such as osteoporosis, osteogenesis imperfecta as well as Paget's disease. Crucial for the proper maintenance of the skeleton is the bone matrix, which encompasses both organic and inorganic components. Osteopontin (Opn) is an example of a major non-collagenous protein present in bone. Its expression is crucial for bone remodeling since it functions in recruiting osteoclasts for bone resorption and facilitates their adhesion to the bone matrix. Osteopontin is expressed in variety of cells and functions in facilitating signal transduction upon engagement of integrin. Osteopontin binds to the αvß3 (vitronectin receptor) the major integrin expressed on osteoclasts thereby mediating cell adhesion and migration. As a model to study osteopontin-mediated adhesion we have employed commercially available osteopontin and the HEK 293 cells that stably overexpress the vitronectin receptor (Vnr cells). We studied the ability of the Vnr cells to adhere to different extracellular matrices including osteopontin. / Bioengineering

No / Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events. Although these processes are still not fully understood, the dysregulation of a number of key proteins must take place if the tumor cells are to disseminate and metastasize. It is now widely accepted that future effective and innovative treatments of cancer metastasis will have to encompass all the major components of malignant transformation. For this reason, much research is now being carried out into the mechanisms that govern the malignant transformation processes. Recent research has identified key genes involved in the development of metastases, as well as their mechanisms of action. A detailed understanding of the encoded proteins and their interrelationship generates the possibility of developing novel therapeutic approaches. This review will focus on a select group of proteins, often deregulated in breast cancer metastasis, which have shown therapeutic promise, notably, EMT, E-cadherin, Osteopontin, PEA3, Transforming Growth Factor Beta (TGF-β) and Ran.