微細な慢性炎症が慢性腎臓病の発症および進展に及ぼす影響に関する研究

広島大学(Hiroshima University)博士(歯学)Doctor of Philosophy in Dental Sciencedoctora

頭頸部扁平上皮癌細胞における表現型の可塑性を介したCD44high細胞の抗癌剤抵抗性のメカニズムの解析

広島大学(Hiroshima University)博士(歯学)Doctor of Philosophy in Dental Sciencedoctora

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.Ana Catarina Ferreira and Sandro Da Mesquita are recipients of PhD fellowships by the Fundação para a Ciência e Tecnologia (FCT, Portugal)/FEDER. Fernanda Marques is an assistant researcher IF/ 00231/2013 of the Fundação para a Ciência e Tecnologia (FCT, Portugal). This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through the project: EXPL/NEUOSD/2196/2013 (to Marques F). The authors thank Nadine Santos for the helpful comments on the manuscript

Identification of RNF213 as a Susceptibility Gene for Moyamoya Disease and Its Possible Role in Vascular Development

もやもや病感受性遺伝子の特定とその機能についての発見. 京都大学プレスリリース. 2011-7-21.Background Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown. Methodology/Principal Findings Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10-4). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10−119). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels. Conclusions/Significance We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease

日本人における家族性脳動脈瘤家系と孤発性脳動脈瘤患者において、9p21上のSNPであるrs1333040との相関を確認

京都大学0048新制・課程博士博士(医学)甲第15940号医博第3525号新制||医||985(附属図書館)28519京都大学大学院医学研究科医学専攻(主査)教授 山田 亮, 教授 松田 文彦, 教授 福山 秀直学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Intramedullary spinal cord abscess and subsequent granuloma formation: a rare complication of vertebral osteomyelitis detected by diffusion-weighted magnetic resonance imaging

An intramedullary spinal cord abscess, which is usually associated with discitis, is an uncommon but potentially important complication of vertebral osteomyelitis. The authors describe a rare case of an intramedullary conus medullaris abscess and lumbar osteomyelitis sparing the intervertebral discs and without discitis. The patient also developed a granuloma in the cauda equina during treatment. Diffusion-weighted MRI was useful for differentiating the granulomatous lesion from the relapse of infection. A 65-year-old immunocompetent man with moderately controlled diabetes presented with progressive lowerextremity numbness and weakness with urinary dysfunction. He had progressive paraparesis, bilateral leg paresthesia, and sphincter compromise. Magnetic resonance imaging revealed an intramedullary ring-enhanced lesion, which was hyperintense on diffusion-weighted images. The lesion, an intramedullary spinal cord abscess, was surgically drained. During antibiotic treatment, serial MRI showed an enlarging enhanced lesion in the cauda equina, and a recurrent infection was suspected. A second-look surgery confirmed the formation of a granuloma and the absence of a relapse of the abscess. Although the enhanced lesion increased in size, its intensity on diffusion-weighted images remained unchanged. After 3 months of antibiotic treatment, all enhanced lesions were diminished. An intramedullary spinal cord abscess is a rare but important complication of vertebral osteomyelitis, and it requires immediate treatment. Diffusion-weighted MRI was useful for the initial diagnosis as well as for monitoring treatment efficacy.</jats:p