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Extracellular RNA in Drug and Diagnostic Development 2016 - 医薬品と診断法開発における細胞外RNA 2016年 -
2016年4月5日 - 2016年4月6日
米国、マサチューセッツ州、ケンブリッジ、ハイアット リージェンシー ケンブリッジ
Extracellular RNA in Drug and Diagnostic Development

生物流体に含まれる細胞外RNA (exRNA) は、正常な細胞過程とそうでない細胞過程の両方に関する豊富な情報を提供してくれます。とりわけ、細胞外小胞に包まれているため劣化しにくいexRNAは、細胞間の情報伝達に関わっており、がんや心血管疾患、神経変性疾患の診断バイオマーカーや予後バイオマーカーとして利用することができます。Cambridge Healthtech Institute (CHI) 主催の第2回Extracellular RNA in Drug and Diagnostic Developmentでは、エキソソーム (エクソソーム) や微小胞、血中循環マイクロRNAなどのノンコーディングRNAを利用した非侵襲的診断の新たな領域における最新の研究成果が発表されることになっており、標準化、プロファイリング、データ分析の課題などをめぐって活発な議論が展開されます。

1日目 | 2日目

4月5日 (火)

12:00 学会の登録手続き


バイオマーカーおよび診断法としての細胞外RNA

1:15 議長による開会の挨拶

Manikkam Suthanthiran, M.D., Stanton Griffis Distinguished Professor, Medicine; Chief, Division of Nephrology and Hypertension, Weill Cornell Medical College

1:20 米国立衛生研究所 (NIH) の細胞外RNAによる細胞間情報伝達についての研究プログラム:治療とバイオマーカー開発のためのexRNA

Danilo A. Tagle, Ph.D., Associate Director for Special Initiatives, National Center for Advancing Translational Sciences, National Institutes of Health

Extracellular RNA (exRNA) can act as endocrine signals to alter the phenotypes of target cells, and represents a novel paradigm in intercellular signaling. RNAseq analyses have identified a diverse population of exRNA that have been linked to regulation of the epigenome which could have profound implications for a wide range of physiologic and pathologic processes. The NIH Extracellular RNA Communication program supports research in exRNA-based biomarker and therapy development, as well as understanding fundamental principles of their biogenesis, distribution, uptake and function.

1:50 がんの機能性バイオマーカーとしてのOncomiR (がん促進型マイクロRNA)

Frank Slack, Ph.D., Director, Institute for RNA Medicine, Department of Pathology, BIDMC Cancer Center, Harvard Medical School

MicroRNAs are excellent candidates for human biomarker studies because their signature short sequences can be easily identified, they are stable in tissue and body fluids, and their expression patterns can be rigorously detected and quantified without harm to the individual. MicroRNAs have been found in multiple body fluids, such as serum and plasma, making them an attractive option for studying non-invasive, blood-based biomarkers. These circulating miRNAs are resistant to RNases and are in fact very stable in an extracellular environment, as they can be packaged in microvesicles, exosomes, or apoptotic bodies. Indeed, profiles of plasma and serum miRNAs have been linked to numerous cancers, and diabetes, indicating that miRNAs are a new class of blood-based biomarkers of human diseases.

2:20 ヒトの同種移植片の状態を予測するために使用可能な細胞外RNAプロファイル

Manikkam Suthanthiran, M.D., Stanton Griffis Distinguished Professor, Medicine; Chief, Division of Nephrology and Hypertension, Weill Cornell Medical College

Liver transplantation is the only lifesaving therapy for patients with irreversible liver failure. A frequent post-transplant complication is acute rejection, currently diagnosed by invasive needle biopsy of the liver allograft. Because miRNAs may serve as biomarkers of clinical disease, we investigated whether circulating extracellular miRNAs in the serum of liver transplant recipients predict human liver transplant status. Our findings support the hypothesis that measurement of circulating levels of extracellular miRNAs offers a noninvasive means of monitoring lifesaving liver transplants.

2:50 スポンサー提供のプレゼンテーション (講演者を募集しています)

3:05 展示会ホールでの休憩、ポスター発表の見学

3:45 肺がん診断のための末梢血単核細胞マイクロRNAバイオマーカー

Feng Jiang, M.D., Ph.D., Professor, Pathology, University of Maryland School of Medicine

Tremendous efforts have been made to develop cancer biomarkers by detecting circulating extracellular miRNAs directly released from tumors. Yet none of the cell-free biomarkers has been accepted to be used for early detection of non-small cell lung cancer (NSCLC). Peripheral blood mononucleated cells (PBMCs) act as the first line of defense against malignancy in the immune system; their dysfunction may occur as an early event in cancer immunogenicity or immune evasion. We proposed to investigate if differential miRNA expressions of PBMCs have diagnostic utility for NSCLC. In a testing set of 56 NSCLC patients and 46 controls, the performance of the biomarkers was reproducibly confirmed and independent of disease stage. The study presents the first in-depth analysis of PBMC miRNA profile of NSCLC patients. The assessment PBMC miRNAs may provide a new diagnostic approach for the early detection of NSCLC.

4:15 アルツハイマー病に対応するバイオマーカーとしての脳脊髄液中マイクロRNA

Julie Saugstad, Ph.D., Associate Professor, Anesthesiology & Perioperative Medicine, Oregon Health & Science University

Alzheimer's disease (AD) is the most common form of dementia. There are currently no clinical biomarkers to confirm the onset of AD, but such a tool would allow earlier initiation of treatments that can slow disease progression. Here, we describe our efforts to identify extracellular microRNAs circulating in cerebrospinal fluid obtained from living donors to serve as biomarkers for AD using quantitative RT-PCR platforms for discovery and validation studies.


トランスクリプトーム解析とデータリソース

4:45 トランスクリプトーム解析

Mark B. Gerstein, Ph.D., Albert L. Williams Professor, Biomedical Informatics, Yale University

This presentation will cover RNA-seq pipelines, RNA-seq clustering techniques, and privacy considerations for RNA-seq data.

5:15 exRNA Communication Consortium (ERCC) が開発したRNA-Seqパイプライン、パスウェイ解析ツール、データリソースによる細胞外RNA機能の研究

Matthew Roth, Ph.D., Assistant Professor & Co-Director, Bioinformatics Research Lab, Baylor College of Medicine; Data Management & Resource Repository of the Extracellular RNA Consortium (NIH)

The NIH funded extracellular RNA Communication Consortium (ERCC) brings together experts in exRNA biology, human disease, bioinformatics, biomarker discovery, and therapeutic development to better understand exRNA biology and potential clinical applications. A key ERCC mission is the development of analytical pipelines and data resources for the broader scientific community. A description of these resources and their application to exRNA analyses will be presented.

5:45 ショートコースの登録手続き


推奨するディナーショートコース *

4月5日 (火) 、18:00〜21:00
(ショートコース3) 免疫反応におけるマイクロRNA

* 別途参加登録が必要です。


1日目 | 2日目

4月6日 (水)

7:45 プレゼンテーションを聞きながらの朝食


バイオマーカーおよび治療法としての細胞外小胞の可能性

8:25 議長の発言

Peter J. Quesenberry, M.D., Director of Research, Division of Hematology/Oncology, Paul Calabresi M.D. Professorship in Oncology at the Warren Alpert Medical School of Brown University and Rhode Island Hospital

8:30 細胞外小胞を利用した治療法としてのマイクロRNA

Peter J. Quesenberry, M.D., Director of Research, Division of Hematology/Oncology, Paul Calabresi M.D. Professorship in Oncology at the Warren Alpert Medical School of Brown University and Rhode Island Hospital

Extracellular vesicles represent a new mode of intercellular communication. We have studies showing that “toxic” endothelial progenitors induced by vesicle exposure can induce pulmonary hypertension (PH) and that mesenchymal stem cell (MSC) derived vesicles can reverse PH. Similarly, normal or MSC vesicles can reverse ischemia-reperfusion renal injury and radiation injury to murine marrow stem cells. MSC or normal vesicles can also reverse the malignant phenotype of prostate and colorectal cancer.

9:00 細胞外RNAとエキソソームによる腫瘍微小環境のがん遺伝子パターンの解析

James G. Patton, Ph.D., Professor, Biological Sciences, Vanderbilt University

Mutant KRAS induces trafficking of EGF receptor (EGFR) and the EGFR ligand amphiregulin to exosomes and drastically changes exosomal protein content, leading to activities that can alter the tumor microenvironment. We characterized small RNAs from cells and matched exosomes that differ only in KRAS status. Exosomal small RNA profiles were distinct from cellular profiles, and mutant KRAS exosomes clustered separately from wild-type KRAS exosomes. miR-100 levels were increased in mutant KRAS cell-derived exosomes and delivery of exosomes with miR-100 downregulated mTOR in recipient cells. Selective trafficking of miRNAs into exosomes appears to be dependent on KRAS-MEK signaling effects on Argonaute 2, a key component of RNA-Induced Silencing Complexes. Besides extracellular RNA transfer, we find that mutant KRAS derived exosomes confer metabolic-altering activity to cells in vitro and in vivo. These findings have implications for non-cell autonomous effects of cancer on the tumor microevironment and the cancer field effect.

9:30 スポンサー提供のプレゼンテーション (講演者を募集しています)

9:45 がん診断、予後、疫学における細胞外小胞の現状と今後の可能性

Mukesh Verma, Ph.D., Chief, Methods and Technologies Branch, National Cancer Institute, National Institutes of Health

Both normal and diseased cells continuously shed extracellular vesicles (EVs) into extracellular space, and the EVs carry molecular signatures and effectors of both health and disease. EVs reflect dynamic changes that are occurring in cells and tissue microenvironment in health and at a different stage of a disease. EVs are capable of altering the function of the recipient cells. Trafficking and reciprocal exchange of molecular information by EVs among different organs and cell types have been shown to contribute to horizontal cellular transformation, cellular reprogramming, functional alterations, and metastasis. EV contents may include tumor suppressors, phosphoproteins, proteases, growth factors, bioactive lipids, mutant oncoproteins, oncogenic transcripts, microRNAs, and DNA sequences. Therefore, the EVs present in biofluids offer unprecedented, remote, and non-invasive access to crucial molecular information about the health status of cells, including their driver mutations, classifiers, molecular subtypes, therapeutic targets, and biomarkers of drug resistance. In addition, EVs may offer a non-invasive means to assess cancer initiation, progression, risk, survival, and treatment outcomes. The goal of this review is to highlight the current status of information on the role of EVs in cancer, and to explore the utility of EVs for cancer diagnosis, prognosis and epidemiology.

10:15 休憩

10:45 大型オンコソーム:がんの細胞間情報伝達に関する新たな研究分野

Dolores Di Vizio, M.D., Ph.D., Associate Professor, Surgery, Biomedical Sciences, Pathology & Laboratory Medicine, Cedars-Sinai Medical Center; Associate Professor, Medicine, University California, Los Angeles; Assistant Professor, Boston Children's Hospital, Harvard Medical School

Our team recently reported that highly metastatic cells export large (1-10 µm diameter) bioactive EVs (large oncosomes) that originate from the shedding of bulky membrane protrusions from the plasma membrane. We have demonstrated that the abundance of large oncosomes in the circulation and in tissues correlate with advanced disease in mouse models and human subjects. Large-scale profile analyses demonstrate that large oncosomes represent a novel population of EVs enriched in tumor-derived molecules. Large oncosomes are thus valuable candidates for new biomarker profiles to be developed using tissue- and blood-based assays in combination.

11:15 個別化医療での血中循環バイオマーカーの臨床評価

Shidong Jia, Ph.D., Scientist, Oncology Biomarker Development, Genentech

The enumeration and characterization of circulating tumor cells (CTCs), exosomes and circulating tumor-free DNA (ctDNA) in the peripheral blood provide important prognostic and diagnostic information in personalized cancer care. Specific examples will be shown to demonstrate the opportunities and challenges for the development of circulating biomarkers in cancer.

11:45 ヒトの神経細胞とグリア細胞培養でのエクソソームノンコーディングRNA発現の系統的プロファイリング

Nikolaos Mellios, M.D., Ph.D., Assistant Professor, Neurosciences, University of New Mexico School of Medicine

Although ignored until recently for not complying with the central dogma of molecular biology, non-coding RNAs (ncRNAs) are emerging as important novel epigenetic regulators of diverse cellular processes. Recent work has revealed the presence of small secretory microvesicles known as exosomes that contain both protein and RNA of the cell of origin and are particularly enriched in ncRNAs. The presence of exosomes in both glia and neurons, and their perceived ability to influence various aspects of neuronal and glial development and function, has positioned them as an exciting and novel method of cell-to-cell communication with important implications for brain disease therapeutics. However, to date, little is known about the exosomal ncRNA expression profile of human neurons and glia. We measured the expression of multiple subtypes of ncRNAs in exosomes isolated from stem cell-derived neuronal and astrocytic cultures, as well as human microglial cultures. Ongoing work is aiming at characterizing the cell-specificity of exosomal ncRNA expression and the association between ncRNAs and protein coding genes secreted by exosomes.

12:15 プレゼンテーションを聞きながらの昼食会または各自で昼食


長鎖ノンコーディングRNAとノンコーディングRNAの可能性

1:25 議長の発言

Da-Zhi Wang, Ph.D., Associate Professor, Cardiovascular Research Division, Department of Cardiology, Boston Children's Hospital, Harvard Medical School

1:30 心血管疾患でのノンコーディングRNA

Da-Zhi Wang, Ph.D., Associate Professor, Cardiovascular Research Division, Department of Cardiology, Boston Children's Hospital, Harvard Medical School

Thousands of long non-coding RNAs (lncRNAs) have been discovered; however, the role of most lncRNAs in heart failure remains largely unknown. We performed RNA deep sequencing from cardiac samples of patients with ICM and controls. Expression correlation coefficient analyses revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. Gain- and loss-of function studies demonstrate that lncRNAs are important regulators of fibrosis. Our results indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ischemic cardiomyopathy.

2:00 長鎖ノンコーディングRNAと腫瘍抑制作用

Nadya Dimitrova, Ph.D., Assistant Professor, Molecular, Cellular, and Developmental Biology, Yale University

There is an unmet need to gain a deeper understanding of the in vivo biology of lncRNAs that are deregulated in disease states, such as cancer. Our laboratory uses genetic approaches to study a subset of lncRNAs that are directly regulated by the important tumor suppressor protein, p53. Our analyses reveal that lncRNAs influence the expression of proteins in the p53 pathway and play key roles in the physiological response to stress and in tumor suppression.

2:30 ノンコーディングRNAを利用したがん細胞脆弱性の特定

Alexander Pertsemlidis, Ph.D., Associate Professor, Pediatrics and Cellular & Structural Biology, University of Texas Health Science Center at San Antonio

To identify ncRNAs that regulate tumor cell viability, we have combined a high-throughput screening platform with libraries of chemically synthesized ncRNA mimics and inhibitors. Candidate targets are validated using qRT-PCR, protein quantification, and luciferase reporter assays. The response of cancer cells to perturbations in candidate ncRNA levels is assessed through flow cytometric analysis of cell cycle phase distribution and through colony formation and caspase activation assays, and validated in mouse xenograft models. We have identified ncRNA mimics and inhibitors that have significant effects on cell viability and drug response. While these ncRNAs may have intrinsic value as biomarkers or therapeutic agents, the vulnerabilities that they uncover are also of value, in that they can be targeted directly with pathway-specific perturbations.

3:00 学会閉幕



1日目 | 2日目

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

 

 


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