Zugl.: Frankfurt (Main), Universiẗat, Diss., 2008.

Univ., Diss., 2009--Marburg.

Universiẗat, Diss., 2005--Frankfurt (Main).

Universiẗat, Diss., 2006--Giessen.

Zugl.: Giessen, Univ., Diss., 2006

Frankfurt (Main), Univ., Diss., 2001.

Universiẗat, Diss., 2002--Frankfurt am Main.

abstract: The need of organs for transplantation has become an increasing medical need due to a limited donor organ supply. Many organs fail within 10 years due to acute and chronic rejection. Acute or antibody mediated rejection leads to decreased long term graft survival and increases the need for a repeat transplant. In prior work, reducing endothelial heparan sulfation and blockade of chemokine-glycosaminoglycan (GAG) interaction with Myxomavirus-derived protein, M-T7, reduced aortic and renal graft vascular inflammation and rejection. Conditional endothelial Ndst1 deficiency and inhibition of chemokine-GAG interaction reduces early allograft damage and suggest new therapeutic options for graft rejection. Here acute renal rejection was examined in grafts with conditional endothelial N-deacetylase-N-sulfotransferase-1 knockout (Ndst1-/-) and in wildtype (WT) C57Bl6/J grafts treated with saline, M-T7, antisense oligonucleotides (ASO) for Ndst1 or a scrambled ASO control. Viruses have a highly adaptive ability to evade hosts defense and immune response. The immunomodulatory proteins derived from viruses provide potential therapeutic uses to alleviate this need for organs. The Myxoma virus derived protein M-T7 is a promising therapeutic for reducing kidney transplant rejection. Orthotopic transplantations in mice are extremely difficult and costly because they require a highly trained microsurgeon. This kidney to kidney subcapsular and subcutaneous transplant model is a practical and simpler method that requires fewer mice, one kidney can be used for transplants in 6 or more mice and there is much lower morbidity, pain and mortality. Heterotopic transplantation of allografts is a simple model for preliminary testing of treatments for early inflammation, ischemia, and graft rejection. Subcapsular kidney transplantation provides a first step approach to test virus-derived proteins as potential treatments to reduce transplant rejection and inflammation. This project reports on a broadly applicable platform on which to rapidly and conveniently test new treatments for transplant rejection. This finding will significantly lower the barrier to entry for labs which are interested in translating their laboratory findings to animal models of organ transplantation which is a complex surgical procedure, and thus accelerate the bench-to-bedside translation of novel, putative treatments for transplant rejection as an initial screening tool. / Dissertation/Thesis / Masters Thesis Molecular and Cellular Biology 2020

Multiple Sclerosis (MS) is a chronic, inflammatory disease of the central nervous system. MS is caused by the immune-mediated destruction of myelin and oligodendrocytes, resulting in demyelination and neurodegeneration. The microRNA miR-145-5p has been demonstrated to be upregulated in MS lesions. Our lab has previously shown that dysregulation of miR-145-5p can interfere with oligodendrocyte differentiation in mice and that knockout of miR-145-5p protects mice from experimental autoimmune encephalomyelitis (EAE), a model for MS. The objective of this study is to determine if inhibition of miR-145-5p with an antisense oligonucleotide (ASO) is sufficient to protect mice from EAE. Female mice were induced with EAE and then treated with a control or miR-145 ASO at the onset of disease. We evaluated disease progression by monitoring clinical severity, and evaluating molecular and structural characteristics of EAE by RT-qPCR, histology, immunohistochemistry and electron microscopy. We have shown that the miR-145 ASO reduced miR-145-5p expression in the lumbar spinal cord, spleen and thymus following EAE induction. Treatment with the miR-145-5p ASO resulted in improved clinical severity of EAE, reduced neuroinflammation and increased myelination. Inhibition of miR-145-5p may represent a novel treatment for MS.

京都大学 / 新制・課程博士 / 博士(医科学) / 甲第25205号 / 医科博第161号 / 新制||医科||11(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 生田 宏一, 教授 伊藤 貴浩, 教授 齋藤 潤 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM