肥満脂肪組織中で増加する特異的T細胞の同定及びTCRトランスジェニックマウスの作製

学位の種別:課程博士University of Tokyo(東京大学

Autopsy Case of Bilateral Optic Nerve Aplasia with Microphthalmia: Neural Retina Formation Is Required for the Coordinated Development of Ocular Tissues

Human congenital anomalies provide information that contributes to the understanding of developmental mechanisms. Here we report bilateral optic nerve aplasia (ONA) with microphthalmia in the autopsy of the cadaver of a 70-year-old Japanese female. The gross anatomical inspection of the brain showed a cotton thread-like cord in the presumed location of the optic nerve tract or chiasm. Histologically, no neural retina, optic nerve bundle or retinal central vessels were formed in the eye globe, and the retinal pigment cells formed rosettes. The cornea, iris, and lens were also histologically abnormal. Immunohistochemically, no retinal cells expressed beta III tubulin, and Pax6-immunoreactive cells were present in the ciliary non-pigmented epithelial cells. This case of ONA could be attributed to the agenesis of retinal projection neurons as a sequel to the disruption of neural retina development. The neural retina formation would coordinate the proper development of ocular tissues

A Synthetic Transcriptional Activator of Genes Associated with the Retina in Human Dermal Fibroblasts.

Small molecules capable of modulating epigenetic signatures can activate the transcription of tissue-restricted genes in a totally unrelated cell type and have potential use in epigenetic therapy. To provide an example for an initial approach, we report here on one synthetic small-molecule compound-termed "SAHA-PIP X"-from our library of conjugates. This compound triggered histone acetylation accompanied by the transcription of retinal-tissue-related genes in human dermal fibroblasts (HDFs)

ニンプ ノ サイガイ ニ タイスル チシキ ボウサイ イシキ オヨビ ボウサイ タイサク ニ カンスル ブンケン レビュー

本レビューは、日本在住妊婦の災害に対する知識や防災意識、防災対策の実態を概観することを目的とした。2022年6月までに公表された和文・英文論文を対象に「妊産婦」「防災対策」に相当する検索語を設定し、電子テータベース検索（医中誌，CiNii，MEDLINE，CINAHL，SocINDEX）およびハンドサーチを行い、8件の論文（和文6件、英文2件）をレビューに包括した。避難場所を知っている妊婦は38.7–63.2%、受診施設以外の近所の産科施設を知っている妊婦は59.6–65.7%、妊娠前より災害への関心が高まった妊婦は約40%であった。非常用持ち出し袋を準備している妊婦は9.7−46.5%であり、2件の論文の定量的統合の結果、初産婦は経産婦に比べて、非常用持ち出し袋を準備している割合が、有意に低かった［オッズ比(95%信頼区間)=0.44 (0.34−0.59)］。以上の結果より、妊娠期は、妊娠前より防災意識が高まる傾向にあること、大半の妊婦が防災対策を行う必要性を感じながらも、防災対策の実施割合は半数前後に留まっていること、初産婦は経産婦に比べ、防災対策の実施割合が低いことが示唆された。総説Review Article

Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay. Evaluation of antiproliferative activity in cancer cells showed that 2 (with a medium linker length of 13-atom) exhibited the highest antiproliferative activity in p53 wild-type cancer cell lines (IC[50] of 1.8–2.6 μM in A549 and MV4-11 cells) and not in p53 mutant cancer cell lines. A mechanistic investigation using microarray analysis and an apoptotic assay showed that the antiproliferative effect of 2 occurred via the up-regulation of p53 target genes, and the subsequent initiation of p53-dependent apoptosis. Our research on sequence-specific dual-target epigenetic repressor offers us an alternative way to modulate HAT-governed therapeutically important genes and contributes to offer a fresh insight into antitumor therapeutics

Targeted Suppression of EVI1 Oncogene Expression by Sequence-Specific Pyrrole-Imidazole Polyamide.

Human ectopic viral integration site 1 (EVI1) is an oncogenic transcription factor known to play a critical role in many aggressive forms of cancer. Its selective modulation is thought to alter the cancer-specific gene regulatory networks. Pyrrole-imidazole polyamides (PIPs) are a class of small DNA binders that can be designed to target any destined DNA sequence. Herein, we report a sequence-specific pyrrole-imidazole polyamide, PIP1, which can target specific base pairs of the REL/ELK1 binding site in the EVI1 minimal promoter. The designed PIP1 significantly inhibited EVI1 in MDA-MB-231 cells. Whole-transcriptome analysis confirmed that PIP1 affected a fraction of EVI1-mediated gene regulation. In vitro assays suggested that this polyamide can also effectively inhibit breast cancer cell migration. Taken together, these results suggest that EVI1-targeted PIP1 is an effective transcriptional regulator in cancer cells