【8th. Jan.】Probe development for systemic molecular imaging of Alzheimer’s disease
日期：2018-01-08
閱讀：2080
Topic: Probe development for systemic molecular imaging of Alzheimer’s disease
Speaker: Dr. Chongzhao Ran, Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School
Time: Monday, January 8, 2018, 13:30 PM
Location: Lecture Hall, Chemistry Building A, Room 528 (化學(xué)A樓528演講廳)
Inviter: Prof. Yong Cui (崔勇教授)
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Abstract：
Probe development for systemic molecular imaging of Alzheimer’s disease
Chongzhao Ran, Ph. D.
Molecular Imaging Laboratory,
Athinoula A. Martinos Center for Biomedical Imaging,
Department of Radiology,
Massachusetts General Hospital
Harvard Medical School, Boston, MA, 02129
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Molecule imaging has been an indispensible tool for diagnosis, pathology investigation and basic mechanism studies in the past decades. For a specific disease, majority of research has been focusing on single-biomarker imaging, which is particularly important for the purpose of diagnosis. However, given the complex nature of diseases, systemic molecular imaging (SYMI) of multi-biomarkers of a single disease can be crucial for understanding the disease, and better designing therapeutics.
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Alzheimer’s disease (AD) is a multi-facet neurodegenerative disease, and its biomarkers are also multi-dimensional. Amyloid beta (Aβ) deposits and tau tangles are
the most typical pathological hallmarks of AD, and Aβ species and tau have been considered to be essential dimensions for imaging AD. However, it is very likely that
other biomarkers also highly correlated with the impaired cognitive functions of AD patients. Among them, reactive oxygen species (ROS) have been widely believed to be an important dimension for AD imaging.
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In this presentation, I will share our recent results on systemic molecular imaging of AD, particularly on the dimensions of Aβs and ROS. On the dimension of Aβ species, it has been intensely debated which sub-species, including insoluble Aβs and soluble Aβs, could be better biomarkers for AD severity and progression. In the past few years, our research has been concentrated on a trilogy of developing “smart” NIRF probes for various Aβ species. For this trilogy, in episode (I) we have effectively developed NIRF probes for insoluble Aβs. In this episode, we have invented a brand-new family of NIR fluorescent dyes CRANAD-X, and some of them are “smart” probes for the insoluble Aβs. In recent years, mounting evidence indicates that the soluble Aβs are probably the most neurotoxic species.
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However, most of the current imaging probes are primarily sensitive for insoluble Aβs. In episode (II), we have successfully developed NIRF probes for both soluble and insoluble Aβ species, and we believe that these probes may have the potential to monitoring the full course of the amyloidosis of AD. For better understanding AD pathology, selectively imaging of the most neurotoxic soluble Aβs is very necessary. In episode (III), we have concentrated our efforts on developing imaging probes selective for soluble Aβs, thus to accomplish early detecting of AD pathology. For the ROS dimension, in the past years, we also have designed several
probes for imaging ROS and H2O2. I will present data to show the correlation of ROS level and the progression of AD.
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Reference
a. Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, Medarova Z, Moore A, J. Amer. Chem. Soc., 2009,131(42):15257-61.
b. Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C.*, J. Amer. Chem. Soc., 2013, 135(44):16397-409.
c. Zhang X, Tian Y, Yuan P, Li Y., Yaseen MA, Grutzendler J, Moore A, Ran C.*, Chem. Commun., 2014, 50(78):11550-3.
d. Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Proc. Natl. Acad. Sci. USA, 2015, 112(31):9734-9.
e. Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C*, Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 2017, 114(47):12384- 12389.
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個人簡歷：
Chongzhao Ran, Ph.D.
冉崇昭博士
Assistant Professor of Radiology
Martinos Center for Biomedical Imaging
Massachusetts General Hospital
Harvard Medical School
Harvard University
Room 2301, Blg. 149
13th Street, Charlestown, MA, 02129
Tel: 617-643-4886
Email: [email protected]
職位
? Assistant Professor of Radiology: Martinos Center for Biomedical Imaging,
哈佛大學(xué)醫(yī)學(xué)院 (2016 - , 分子影像學(xué))
? Instructor of Radiology, Martinos Center for Biomedical Imaging,
哈佛大學(xué)醫(yī)學(xué)院 (2009 -2016 , 分子影像學(xué))
教育背景
? 博士后: Martinos Center for Biomedical Imaging,
哈佛大學(xué)醫(yī)學(xué)院 (Sept.2006- Oct. 2009, Molecular Imaging)
Ben May Institute for Cancer Research,
芝加哥大學(xué) (2002 ~ 2006, 生物有機化學(xué) 與癌癥研究)
? 博士: 上海醫(yī)藥工業(yè)研究院 (1997.9 ~ 2000.8, 藥物化學(xué))
? 碩士: 中國藥科大學(xué) (1994.9 ~ 1997.7, 藥物化學(xué))
? 本科：中南民族大學(xué) (1990.9 ~ 1994.7, 有機化學(xué))
研究項目
? 開發(fā)可?于?年癡呆早期診斷的分?影像技術(shù)：?年癡呆癥是?種尚?法治愈的神經(jīng)退?性疾病. 隨著社會???齡化，?年癡呆患者將不斷的增加，因?該疾病將給社會帶來沉重的醫(yī)療負(fù)擔(dān)。目前，尚?藥物可以減緩或治愈?年癡呆。?于臨床治療的藥物僅僅可以改善癥狀，但不能阻?該疾病的惡化進(jìn)程和延??命。因?，開發(fā)可以減緩或治愈?年癡呆的藥物是?項?常緊迫的任務(wù)。為了有效地開發(fā)針對?年癡呆的藥物，尋找能夠跟蹤和檢測?年癡呆病理變化的分?影像技術(shù)愈發(fā)顯得重要。
分?影像技術(shù)是?類?靈敏和?損傷性的活體檢測和診斷技術(shù)，開發(fā)針對?年癡呆的熒光分?影像探針，PET（正電?斷層掃描技術(shù)）和MRI (核磁共振）分?影像探針將有助于加快藥物開發(fā)的進(jìn)程和有效性。
該項目以姜?素為先導(dǎo)化合物，設(shè)計合成了?系列熒光分?探針并進(jìn)?了活體動物影像實驗，發(fā)現(xiàn)了?個能夠有效進(jìn)?在體跟蹤?年癡呆病理變化的探針 CRANAD-Xs。為了實現(xiàn)臨床轉(zhuǎn)化，我們還設(shè)計合成了?系列18F 標(biāo)記PET 探針，并進(jìn)?了PET 動物成像實驗。實驗結(jié)果表明其中?些PET 探針可以有效區(qū)分轉(zhuǎn)基因?年癡呆??和正常??。有關(guān)MRI 探針的設(shè)計合成正在進(jìn)?之中。我們的實驗結(jié)果表明所設(shè)計的熒光分?探針可以有效地跟蹤?年癡呆模型?病程變化，并且能夠可靠地監(jiān)測實驗藥物的治療效果。我們認(rèn)為我們的熒光分?影像技術(shù)將??地提??年癡呆藥物開發(fā)的效率。
? 針對?年癡呆的藥物開發(fā)：該項?以姜?素為先導(dǎo)化合物，設(shè)計合成了?系列衍?物，并進(jìn)?了?年癡呆模型?體內(nèi)藥效實驗。利?我們的熒光分?影像技術(shù)進(jìn)?跟蹤實驗，結(jié)果表明其中?些化合物可以有效地抑制病程發(fā)展。我們的成像跟蹤結(jié)果與傳統(tǒng)的病理分析結(jié)果?致。
? 開發(fā)可以監(jiān)測棕?脂肪的分?影像技術(shù)：近?年來，?規(guī)模的臨床試驗和統(tǒng)計分析表明棕?脂肪與?類的體內(nèi)代謝有著極其重要的關(guān)系。與健康試驗者相?，糖尿病和肥胖患者的棕?脂肪重量明顯偏低。因?有?提出增加棕?脂肪重量將有利于這些疾病的治療。但是，能夠可靠地監(jiān)測棕?脂肪重量變化的?法目前還不成熟。該項?通過?量篩選熒光分?探針發(fā)現(xiàn)了CRANAD－2 可以?于??體內(nèi)棕?脂肪的成像，但是該熒光探針不能夠有效地區(qū)分棕?脂肪和??脂肪（有害脂肪）。我們通過對該分?的修飾和改造，成功地找到了?個?選擇性?靈敏度的熒光分?。我們在不同的疾病模型上使?這些分?，發(fā)現(xiàn)這些熒光探針能夠有效地監(jiān)測棕?脂肪重量的變化。目前的試驗結(jié)果表明，我們的技術(shù)可以?泛?于棕?脂肪的臨床前研究。
所獲榮譽
? 1993 Top Student, South-Central University for Nationalities, Wuhan, China
? 1994 Honored Student, South-Central University for Nationalities, Wuhan,
? 1996 Jiuhuan Award, China Pharmaceutical University, Nanjing, China
? 2008 Travel Award, World Molecular Imaging Congress, 2008, Nice, France
? 2010 Career Development award from NIH/NIA
專利申請
1. Ran, C., Moore, A., 2008, Difluoroboron-derivated Curcumin as a near infrared probe, PCT Int.Appl. (2010), WO 2010017094 A2 20100211.
2. Xie, M. Ran, C., Ming, Y., 2008, Tetrahydroisoquinoline as potential antiarrhythamic agent ,CN101619038.
3. Ran, C., Moore, A., 2009, Methods and system for detecting soluble amyloid-β, PCT Int.Appl. (2011), WO 2011014648 A2 20110203.
4. Ran, C., Moore, A., 2013, Methods and system for imaging Brown Adipose Tissue, US Patent No.:US 14/916,779, PCT/US2014/054012.
5. Ran, C., Moore, A., 2012, Rational design curcumin analogues to attenuate copper induced crosslinking of amyloid beta, US Patent number: 9738623.
6. Ran, C., Yang, J., Moore, A., 2016, Half-curcuminoids as potential amyloid-beta PET imaging agents (MGH Invention No. 24074)
發(fā)表學(xué)術(shù)論文（部分論文）
1) Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C*, Oxalate-curcumin based probe for micro- and macro-imaging of reactive oxygen species in Alzheimer’s disease, Proc.Natl. Acad. Sci. USA, 2017, 114(47):12384-12389.
2) Yang J, Zhang X, Zhu Y, Lenczowski E, Tian Y, Yang J, Zhang C, Hardt M, Qiao C, Tanzi RE, Moore A, Ye H, Ran C*, A double-edged role of copper in the fate of amyloid beta in the presence of antioxidants,Chemical Science, 2017, 8: 6155-6164.
3) Li Y, Yang J, Liu H, Yang J, Du L, Feng H, Tian Y, Cao J, Ran C*, Tuning Stereo-hindrance of Curcumin Scaffold for Selective Imaging of Soluble Forms of Amyloid Beta Species, Chemical Science, 2017, 8:7710-7717.
4) Shen S, Lim G, You Z, Ding W, Huang P, Ran C, Doheny J, Caravan P, Tate S, Hu K, Kim H, McCabe M, Huang B, Xie Z, Kwon D, Chen L, Mao J, Gut microbiota is critical for the induction of chemotherapy-induced pain, Nature Neuroscience, 2017, 20(9):1213-1216.
5) Zhang X, Tian Y, Zhang H, Kavishwar A, Lynes M, Brownell AL, Sun H, Tseng YH, Moore A, and Ran C*, Curcumin analogues as selective fluorescence imaging probes for brown adipose tissue and monitoring browning, Scientific Reports, 2015, 5: 13116, doi:10.1038/srep13116.
6) Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Near‐infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease, Proc. Natl. Acad. Sci. USA, 2015, 112(31):9734-9. PMID: 26199414.
7) Zhang X, Tian Y, Yuan P, Li Y., Yaseen MA, Grutzendler J, Moore A, Ran C.*, A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease, Chem. Commun., 2014, 50(78):11550-3. PMID: 25134928.
8) Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C.*, Design and Synthesis of Curcumin Analogues for in Vivo Fluorescence Imaging and Inhibiting Copper-Induced Cross-Linking of Amyloid Beta Species in Alzheimer's Disease, J. Amer. Chem. Soc., 2013, 135(44):16397-409.
9) Xueli Zhang, Chaincy Kuo, Anna Moore, C Ran*, In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging, PLOS One, 2013, 8(4): e62007.
10) C Ran, Anna Moore, Spectral Unmixing Imaging of Wavelength-Responsive Fluorescent Probes: An Application for the Real-Time Report of Amyloid Beta Species in Alzheimer's Disease, Mol. Imaging and Biology, 2012,14(3): 293-300.
11) C Ran, Xiaoyin Xu, Pamela Pantazopoulos, Zdravka Medarova, Brian J. Bacskai, Anna Moore, Design, Synthesis and Testing of Curcumin Based “Smart” Near Infrared Probes for in vivo Detection of Amyloid-β Plaques in Transgenic Animal Model, J. Amer. Chem. Soc., 2009, 131(42):15257-61.
12) C Ran, Qing Dai, and Ronald G. Harvey, Strategies for Synthesis of Adducts of o-Quinone Metabolites of Carcinogenic Polycyclic Aromatic Hydrocarbons with 2'-Deoxyribonucleosides, J. Org. Chem., 2008,73 (3), 992 -1003.
13) C Ran, Pamela Pantazopoulos, Zdravka Medarova, Anna Moore, Synthesis and Testing of Beta-Cell-Specific Streptozotocin-Derived Near-Infrared Imaging Probes, Angewandte Chemie International Edition, 2007, 46(47): 8998-9001.
14) C Ran, Qing Dai, Ronald G. Harvey, Efficient synthesis of N6-aryl-2'-deoxyadenosines via coppermediated direct coupling of aryl halide with 2'-deoxyadenosine. J. Org. Chem., 2005, 70(9): 3724-26.
15) Qing Dai, C Ran, Ronald G. Harvey, Synthesis of adducts of o-quinone metabolites of Carcinogenic polycyclic aromatic hydrocarbons with 2’-deocyadenosine and 2’-deoxyuanosine. Organic Letters, 2005, 7(6): 999-1002.
會議報告 （部分報告）
1) Xueli Zhang, Anna Moore, C Ran*, Curcumin analogues for fluorescence imaging and inhibiting cross-linking of amyloid beta of Alzheimer’s disease. New Advances in optical imaging in cell and organism, 2013, Cold Spring Harbor Laboratory Meeting, Asia, Suzhou (Contribution Presentation).
2) Xueli Zhang, Anna Moore, C Ran*, Imaging Brown Adipose Tissue with Cerenkov Luminescence Imaging, World Molecular Imaging Congress, 2012, Dublin, Ireland ((Selected Oral Presentation by the Committee).
3) C Ran, Anna Moore, Smart optical imaging probes for AD detection, World Molecular Imaging Congress, 2010, Kyoto, Japan (Selected Oral Presentation by the Committee).
4) C Ran, Anna Moore, Non-conjugated small molecular FRET for differentiating Abeta species, World Molecular Imaging Congress, 2010, Kyoto, Japan ((Selected Oral Presentation by the Committee).
5) C Ran, Xiaoyin Xu, Anna moore, Design, synthesis, and testing of difluoroboron derivated curcumins as “Smart” Near Infrared Probes for in vivo detection of amyloid-β deposits, World Molecular Imaging Congress, Nice, France, 2008 (Selected Oral Presentation by the Committee).
邀請報告 （部分報告）
2010 Shanghai Jiaotong University, Shanghai, China
Molecular Imaging in detection of pathology of Alzheimer’s disease
2010 Shandong University, Jinan, China
Molecular Imaging and Chemical Biology
2011 South-Central University for Nationalities, Wuhan, China
Molecular Imaging in detection of pathology of Alzheimer’s disease
2012 Caliper Lifescience, MA, USA (Workshop at Yale University)
Fluorescence imaging of Alzheimer’s disease
2013 Martinos Center for Biomedical Imaging, MGH/Harvard Medical School
Near-infrared “smart” fluorescent imaging probes for amyloidosis of Alzheimer’s disease
2013 Pfizer Pharmaceuti
