東京大学医科学研究所

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開催日時: 2016年8月25日 17:00~ 18:30
開催場所: 2号館2F 小講義室
講師: 1部 Antoine Gessain
2部 Lloyd Einsiedel
所属: Antoine Gessain
Institut Pasteur, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie / Chef d'Unité
Lloyd Einsiedel
Aboriginal Health BakerIDI, Alice Springs Hospital / Associate Director of Research

演題: 1部 Origin of HTLV-1 infection in Central Africa: Importance of interspecies transmission through severe bite from Gorilla.
2部 The Human T Lymphotropic Virus type 1 subtype c: a major cause of morbidity and mortality for socially disadvantaged Indigenous Australians

概要:

1部  HTLV-1 is not a ubiquitous virus. Indeed, this retrovirus, whose origin is the STLV-1, endemic in many species of Old-World non human primates (NHPs), is present throughout the world with clusters highly endemic located often nearby areas where the virus is nearly absent. The main endemic areas are the Southwestern part of Japan, Sub-Saharan Africa and South America, the Caribbean area and foci in the Middle East and Australo-Melanesia. The origin of this puzzling repartition geographical or sometimes rather ethnic repartition is probably linked to a founder effect in some groups with the persistence of a high viral transmission rate. Despite different socio-economic and cultural environment, the HTLV-1 prevalence increases gradually with age, especially among women in nearly all highly endemic areas. The number of HTLV-1 infected carriers in the world is estimated to be at least 5-10 millions individuals. In most of the high endemic areas, HTLV-1 is mainly disseminated and maintained in the human population through intra-familial transmission (mother-to-child and by sexual intercourses). More rarely, transmission may also occur by transfusion or intra-venous drug use. In Central Africa, the relative contribution of each of the different transmission routes for HTLV-1/STLV-1 (inter-humans vs inter-species/NHP-Humans) still remains largely unexplored. We have thus performed epidemiological studies in order to get better knowledge on the possible still ongoing STLV-1 retroviral transmission from NHPs to human in a natural setting. These studies were done in populations of high-risk individuals living in villages or settlements in the rain-forest of South Cameroun and Gabon. Bantu and Pygmy groups, who still actively hunt diverse NHP species, inhabit this region. These hunters are thus frequently exposed to the body fluids of these NHPs. Furthermore, many of the NHPs species living in these areas are infected with simian retroviruses, including various STLV-1 strains. Our main results indicate that a severe bite by a NHP is a major risk factor for HTLV-1 infection in these hunters. Furthermore, some of the HTLV-1 strains present in hunters bitten by a NHP are very closely related to some of the STLV-1 strains present in NHPs from the same areas. Indeed, all the HTLV-1-positive hunters bitten by a gorilla or a chimpanzee were infected with a subtype B strain similar to that present in apes from the same areas. Two hunters bitten by small monkeys (C. agilis in one case) were infected with an HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities.

1) Filippone C, Betsem E, Tortevoye P, Cassar O, Bassot S, Froment A, Fontanet A, Gessain A. A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa. Clin Infect Dis. 2015 Jun 1;60(11):1667-76.
2) Kazanji M, Mouinga-Ondémé A, Lekana-Douki-Etenna S, Caron M, Makuwa M, Mahieux R, Gessain A. Origin of HTLV-1 in hunters of nonhuman primates in Central Africa. J Infect Dis. 2015 Feb 1;211(3):361-5.
3) Richard L, Mouinga-Ondémé A, Betsem E, Filippone C, Nerrienet E, Kazanji M, Gessain A. Zoonotic transmission of two Human T lymphotropic virus type 4 strains in hunters bitten by gorillas in Central Africa. C Infect Dis, in press, 2016.

2部 The Human T Lymphotropic Virus type 1 has a global prevalence, however, most people living with HTLV-1 reside in clusters of high endemicity in resource poor countries. One such endemic focus is present in central Australia where infection with the Australo-Melanesian HTLV-1c subtype is highly prevalent among Indigenous Australians. Australia is therefore one of few countries in which a socially disadvantaged population with a high HTLV-1 prevalence coexists with a sophisticated medical system. Studying the consequences of HTLV-1 infection in this setting may therefore provide insights relevant to resource poor HTLV-1 endemic areas elsewhere.
The prevalence rate of HTLV-1 infection among Indigenous Australians exceeds 40% among Indigenous adults residing in some remote communities. An increased risk of infection among older men is unique among epidemiological studies. In central Australia, cases of Adult T-cell leukemia and HTLV-1 associated myelopathy have been reported. However, HTLV-1 infection is most often associated with chronic respiratory disease and invasive bacterial infections. The region has the highest reported prevalence of adult bronchiectasis worldwide and 60 of 106 subjects (56.7%) in this cohort are HTLV-1 infected. We have demonstrated that the risk of bronchiectasis and the extent of pulmonary injury is strongly associated with the HTLV-1 proviral load. In a region with among the highest reported incidence rates of invasive bacterial disease worldwide, a higher HTLV-1 proviral load is a major predictor of a blood stream infection. A well characterized, hospital-based cohort of 843 Indigenous adults of known HTLV-1 serostatus has now been followed prospectively for up to eight years. In this cohort, an HTLV-1 proviral load 1000/100,000 copies per 105 peripheral buffy coat cells was associated with a significant increase in risk of death, which most often resulted from complications of bronchiectasis or sepsis.
In this presentation, the epidemiology, clinical associations and outcomes of HTLV-1 infection in central Australia will be described. Research seeking to elucidate the immunological basis for the heightened risk of bacterial infection is ongoing. However, repeated exposure to virulent pathogens is an inevitable consequence of the poor social circumstances of many people living with HTLV-1 and this may play a major role in the outcome of HTLV-1 infection in resource poor areas.


世話人: ○内丸 薫(病態医療科学分野)
 四柳 宏(感染症分野)
開催日時: 2016年7月4日 17:00 ~ 18:00
開催場所: 総合研究棟4階 4306共用会議室
講師: Dr. SANO, Teruyuki
所属: New York University School of Medicine
演題: 共生細菌により誘導されるTh17細胞の分化とその活性化の分子機構
概要:

腸は解剖学上、外界と接している最大にして最も複雑な免疫器官である。人の腸内には数1000種類、100兆個を超える共生細菌が生息しており、 これらの共生細菌と腸管免疫細胞は互いに制御しあい腸管内の恒常性を保っている。近年ではこの共生細菌の異常が、自己免疫疾患、精神疾患などの様々な疾患に関与していることが報告されてきた。しかしながら、腸管粘膜における免疫系がどのように共生細菌と相互作用し、分化誘導及び活性化されるかは未だ不明な点が多い。
本講演ではCD4+ T細胞のサブセットであるTh17 細胞を分化誘導するユニークな共生細菌「SFB」に着目することで、Th17細胞の分化及びその活性化の分子機構について解説し、いかにして共生細菌由来のTh17細胞が病原性を獲得し、腸管における炎症性疾患だけでなく、様々な組織における自己免疫疾患、炎症性疾患にどのように関与するかの議論を深めたい。

世話人: ○清野 宏 (炎症免疫学分野)
 三宅 健介 (感染遺伝学分野)
開催日時: 2016年7月19日 16:00~17:00
開催場所: 2号館 大講義室
講師: 常盤 広明
所属: 立教大学理学部化学科 未来分子研究センター・教授
演題: 「見て、触って、閃いて!
3Dプリンタにより、今開かれる「計算ウイルス学」の世界」
概要:

現在社会をとりまくデジタル環境の変化はすさまじく、クラウドサーバーやモバイル端末など、創薬に利用可能なデジタルデータや機器にも、急速に多様化の波が押し寄せている。そのような中、合理的創薬の基本的となる構造基盤型アプローチにおいて、標的タンパク質に適合する薬物候化合物を効率的に設計する場合、タンパク質-薬物相互作用を視覚的評価、理解するために、コンピュータによる分子モデリング用ソフトウエアや分子模型が活用されている。しかし、前者は複雑な操作の熟達が必要であり、実際に立体的イメージを把握するためには「回転」などの操作が必要であり、構造の裏側や結合ポケットの深さなどは分かりにくかった。また後者は、実体を掴むことはできても結合ごとに作成するため、タンパク質など大きな分子には不向きであった。その一方で、以前にScripps研究所やNIH-FEIなどにおいて、ウイルス模型の作成に利用された3Dプリンタのダウンサイジングが急速に進み、一般的なラボレベルでも利用が可能となってきた。本研究では、3Dプリンタを用いて、創薬標的であるインフルエンザ表面タンパク質の結合ポケットモデルや薬物候補化合物の新規3D模型を具体的に紹介し、3Dプリンタの持つ無限ポテンシャル[1]が切り開く新規創薬カテゴリについて述べる。さらに、3Dプリンタのウイルス学研究への応用について紹介する。
1. Jones Nicola, Nature 487, 23 (2012).

世話人: ○河岡 義裕(ウイルス感染分野)
 川口 寧(ウイルス病態制御分野)
開催日時: 2016年8月8日 16:00 ~ 17:30
開催場所: 2号館 小講義室
講師: Victor Appay
所属: Research Director, National Institute for Health and Medical Research (INSERM), Team ‘Pathogenesis of chronic infections and immune aging’, Immunity and Infectious Diseases Research Center, the Pierre et Marie Curie University (UPMC)
演題: Decline of Immunity with Aging in Humans
概要:

Life expectancy in the world has nearly doubled over the last century. However, aging is associated with the onset of multiple co-morbidities. Elderly people present increased susceptibility to infectious and malignant diseases, and impaired vaccine efficacy. This is most likely related to the decline of the immune system with age, or immunosenescence. A better understanding of the causes and consequences of immune aging is therefore a public health priority. In recent years, we have characterized immune cell compartments in the elderly, exploring putative causes of their decline in relation to elevated inflammation and chronic viral infections, and studying potential consequences on cellular immune competence with advanced age. Old individuals display an altered hematopoiesis and decreased lymphocyte replenishment associated with an exhaustion of primary immune resources (down to the level of hematopoietic progenitors). Using an original in vitro approach to examine T-cell priming efficacy in humans, we also show that old individuals consistently mount impaired de novo CD8+ T-cell responses against a melanoma antigen, which likely reflects reduced immuno-surveillance against cancer with advanced age. Overall, our work highlights the complexity of immune aging in humans, characterized by a combination of immune cell alterations, and the necessity to develop tailored immunotherapy and vaccine strategies in the elderly.

世話人: ○俣野 哲朗 (附属病院 エイズワクチン開発担当・委嘱教授)  
 川口 寧 (ウイルス病態制御分野・教授)
開催日時: 2016年7月20日 16:00~17:00
開催場所: 総合研究棟 4階セミナー室
講師: 新崎 恒平
所属: 東京薬科大学・生命科学部・講師
演題: 栄養状態においてsyntaxin 17はミトコンドリアの切断に関与する
概要:

2012年、東京大学の水島教授らのグループはsyntaxin 17 (Stx17)がオートファゴソームとリソソームの融合に機能することを報告した。また、その翌年には大阪大学の吉森教授らのグループはStx17が小胞体—ミトコンドリア接触部位(MAM)におけるオートファゴソーム形成に機能していることを報告した。このことから、Stx17はオートファジーの進行において多彩な機能を発揮していることが明らかとされた。
 
我々は、栄養状態のStx17の機能に着目して解析を行い、栄養状態においてStx17は小胞体・MAM・ミトコンドリアに局在し、ミトコンドリアの分裂因子であるDrp1と協調し、ミトコンドリアの分裂に寄与することを見いだした (1)。また、細胞が栄養飢餓状態に陥るとStx17の結合パートナーがDrp1からAtg14L(オートファゴソーム形成に関わるPI3PKの構成因子)に変換することも明らかにした。本結果は、Stx17がMAMにおける分子スイッチとして種々の生理機能に関わっていることを示している。

1. Arasaki et al. A role for the ancient SNARE syntaxin 17 in regulating mitochondrial division. Dev Cell. 2015

世話人: ○一戸 猛志(ウイルス学分野)
河岡 義裕(ウイルス感染分野)
開催日時: 2016年7月13日 11:00~ 12:00
開催場所: 病院棟8階 南会議室
講師: Dr. Ari M. Melnick
所属: Gebroe Professor of Hematology and OncologyChair, Hematologic Malignancies Program Sandra and Edward Meyer Cancer Center Director, Sackler Center for Biomedical and Physical Sciences Departments of Medicine and Pharmacology, Weill Cornell Medical College
演題: The role of the epigenome in pathogenesis and therapy of acute myeloid leukemia
概要:

Aberrant epigenetic patterning of the genome is emerging as a hallmark of acute myeloid leukemia, a malignancy characterized by a relative paucity of genetic lesions. AML can be classified into disease subtypes based on DNA methylation signatures. The most informative methylcytosine residues driving epigenetic clustering of AML patients are located in enhancer elements, positioned outside of CpG islands. Hence perturbation of enhancer function through aberrant cytosine methylation may play a key role in encoding the unique phenotypes and clinical outcomes of subsets of AML patients. We predicted that epigenetic signatures could be used as molecular blueprints that point towards causative mechanisms that drive leukemia phenotypes. Along these lines a subset of AMLs that share a particular DNA hypermethylation signature exhibit somatic mutations of the IDH1 and IDH2 genes, which generate the oncometabolite 2-hydroxyglutarate, which can inhibit aKG dependent dioxygenases including the TET family of enzymes that convert 5-methylcytosine into 5-hydroxymethlcytosine. Indeed patients with TET2 mutations share the aberrant DNA methylation profile of IDH mutant AML patients. We found that WT1, a transcriptional regulator often mutated in AML interacts with TET2. Notably, somatic mutations in IDH1, IDH2, TET2 and WT1 are almost universally mutually exclusive of each other in AML. Patients with all four of these mutations exhibit reduced global levels of 5hmC and in genome wide profiling studies display overlapping 5hmC distribution profiles. Collectively these data define a functional axis whereby WT1 mutation defines a subset of the effects emanating from TET2 loss of function, which in turn mediates a subset of the actions of 2HG generated by mutant IDH1 and IDH2. Although loss of TET2 does not cause AML in mice, leukemia does occur when TET2 deficient mice are crossed with FLT3ITD transgenic animals. Methylome analysis revealed that TET2 or FLT3-ITD alone had little effects on cytosine methylation alone. However both together resulted in a massive hypermethylation signature distinct from those affected by either mutation alone. Most of this perturbation consisted of DNA hypermethylation. Among the top methylated genes was GATA2, which was silenced in the double but not single mutant animals, as well as human TET2 + FLT3ITD AML patients. Restoration of GATA2 rescued the TET2-FLT3ITD leukemia phenotype, demonstrating that loss of GATA2 plays a critical role in the biological effect of the combined mutations. The inherent plasticity of the epigenome could potentially endow populations of AML cells with epigenetic heterogeneity and hence greater opportunities to encode chemotherapy resistant phenotypes. We developed an approach to identify epigenetic “alleles” that could be assessed to determine AML “epi-clonality”. Indeed we observed that epigenetic allele burden is linked to unfavorable clinical outcome in AML, independent of somatic mutations or other biomarkers. Genetic and epigenetic allelic diversity did not track together and appeared to be distinct biological phenomenon. AMLs could be classified into those with high epiallele burden with low somatic mutations, and a second group with low epiallele burden and higher somatic mutation burden. The presence of epialleles was accompanied by transcriptional deregulation as shown by single cell RNA-seq profiling. The presence of epigenetic allele diversity may thus enable AMLs to sample different transcriptional states.

世話人: ○北村 俊雄(細胞療法分野)
 中西 真(癌防御シグナル分野) 
開催日時: 2016年7月15日 15:00 ~ 16:00
開催場所: 病院棟8階 北会議室
講師: Teru Hideshima
所属: Principal Associate in Medicine, Harvard Medical School Senior Scientist, Dana-Farber Cancer Institute
演題: Understanding multiple myeloma pathogenesis in the bone marrow microenvironment
概要:

Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by accumulation of monoclonal plasma cells in the bone marrow (BM) with complex heterogeneous cytogenetic abnormalities. It remains incurable and novel biologically based therapies are urgently needed. Similar to other cancers frequently causing bone metastases (ie., breast, prostate and lung cancers), MM cells interact with different types of cellular components, including BM stromal cells, osteoblast, osteoclast and vascular endothelial cells in the BM microenvironment. The interaction of MM cells with these cells is mediated by soluble factors (i.e., cytokines, chemokines) and cell-cell contact via cell adhesion molecules (i.e., integrins). This interaction triggers activation of intracellular signaling pathways in MM cells, such as Ras/MEK/ERK, Jak2/STAT3, PI3K/Akt and IKK/NF-κB cascades. It also induces cell adhesion-mediated drug resistance (CAM-DR) to overcome conventional therapeutic agents. Moreover, existence of crosstalk between these signaling cascades shows the complexity of signal transduction network in MM cells in the BM microenvironment. Importantly, MM cells also mediate activation, differentiation and/or proliferation of osteoblast and osteoclast. Targeting the BM microenvironment therefore represents a novel therapeutic strategy in MM. Indeed, novel therapeutic agents have been showing remarkable clinical activities in MM patients by targeting both MM tumor cells and their BM microenvironment.

世話人: ○東條 有伸 (分子療法分野)
 安井 寛 (先端ゲノム医療の基盤研究寄付研究部門)
開催日時: 2016年6月27日 17:00~18:00
開催場所: 2号館2階 大講義室
講師: Nadav Ahituv
所属: Associate Professor, Department of Bioengineering and Therapeutic Sciences, Institute of Human Genetics University of California San Francisco
演題: Functional Characterization of Gene Regulatory Elements
概要:

Nucleotide variation in gene regulatory elements is a major determinant of phenotypes including morphological diversity between species, human variation and human disease. Despite continual progress in the cataloging of these elements, little is known about the code and grammatical rules that govern their function. Deciphering 6-27the code and their grammatical rules will enable high-resolution mapping of regulatory elements, accurate interpretation of nucleotide variation within them and the design of sequences that can deliver molecules for therapeutic purposes. To this end, we are using massively parallel reporter assays (MPRAs) to simultaneously test the activity of thousands of gene regulatory elements in parallel. By designing MPRAs to learn regulatory grammar or to carry out saturation mutagenesis of every possible nucleotide change in disease causing gene regulatory elements, we are increasing our understanding of the phenotypic consequences of gene regulatory mutations. To better understand how nucleotide changes in gene regulatory elements lead to morphological differences between species, we are using the developing bat wing as a model. Using a combination of whole-genome sequencing, RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on developing bat forelimbs and hindlimbs at three sequential embryonic stages, we are attempting to decipher the molecular events that underlie bat wing development.

世話人: ○古川 洋一
 中井 謙太
開催日時: 2016年7月5日 10:30~11:30
開催場所: 総合研究棟4階 4306共用会議室
講師: PANDA, Satchidananda
所属: Professor, the Regulatory Biology Laboratory Salk Institute for Biological Studies
演題: Circadian regulation of metabolism for the prevention and treatment of metabolic diseases
概要:

Diurnal rhythm in eating and fasting without changing nutrient quantity is known to improve oscillations in metabolic pathways, which in turn temporally separates incompatible processes. Preventing obesity with time-restricted feeding (TRF; 8-9h food access in the active phase) in nocturnal rodents is promising, yet its therapeutic applicability against preexisting obesity, diverse nutritional challenges, and less stringent eating patterns is unknown. TRF in Drosophila maintained body weight, improved sleep, and delayed age-dependent or high fat induced decline in cardiac performance. The beneficial TRF effect on cardiac function was dependent on a functional circadian clock and was partly mediated by ATP-dependent chaperone function. In rodents, TRF attenuated metabolic diseases arising from a variety of obesogenic diets. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with pre-existing obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia. Unbiased assessment of the temporal changes in transcriptome, metabolome and gut microbiome revealed temporal eating pattern exerts pleiotropic effect on metabolism in multiple tissue types.

世話人: ○清野 宏 (炎症免疫学分野)
 三宅 健介 (感染遺伝学分野)
開催日時: 2016年6月28日 17:00~18:30
開催場所: 2号館 小講義室
講師: 上野 博夫
所属: 関西医科大学 病理学第一講座・教授
演題: 細胞系譜解析からみた成体幹細胞の発生、維持とがん化について
概要:

成体組織特異的幹細胞研究は、再生医療への応用だけでなく、生体内においてがん化、老化、障害再生等の重要な生命現象の鍵となる機能を担っており、そうした現象のメカニズム解明のためにも、極めて重要である。しかしながら、成体組織特異的幹細胞の内、解析の進んでいるものは骨髄内造血幹細胞、腸上皮幹細胞、皮膚幹細胞、神経幹細胞、精巣生殖幹細胞など比較的細胞代謝の早い一部に過ぎない。一方細胞代謝の遅い臓器など、解析の難しさからこれまで組織幹細胞の同定そのものがなされていない臓器や解析が進んでおらず幹細胞の性質がよくわかっていない臓器は多く存在している。しかしそうした解析の進んでいない臓器、組織の中にも悪性腫瘍の頻度等から重要なものは多く残されており、近年一部のがんの分子標的療法など先端治療法が開発される状況において、治療可能な悪性腫瘍のレパートリーを増やして行くためにも、各組織における成体幹細胞の同定と機能解析、遺伝子発現プロファイルの解析などの重要性が改めて注目されているところである。
 
演者は2006年以降テトラキメラ法、レインボーマウスといった多色細胞系譜追跡法を開発して幹細胞の発生および成体における維持機構、がん化機構について解析を行ってきた。こうした多色細胞系譜追跡法の大きな利点の一つは幹細胞の存在だけでなく、幹細胞のクローナリティをin vivo、in situにて容易に視覚化できる点にある。さらにオルガノイド培養などを組み合わせればin vitroにて、また組織によっては生体外より直接time lapse imagingにて幹細胞の動態解析が可能である。演者はこうした方法論を用いて各種成体組織幹細胞の維持機構、がん化におけるその破綻について解析を加えて来た。また、これらの方法にて新しい成体幹細胞の同定にも成功している。本講演にては演者の研究室で同定された舌上皮幹細胞をモデルとして取り上げ、これら新しい研究の流れと現状について紹介したい。

世話人: ○北村 俊雄
 中西 真