Chongzhao Ran, PhD

Professional Information

Experience: 

Assistant Professor in Radiology, Harvard Medical School
Assistant in Neuroscience, Massachusetts General Hospital

Education: 

PhD Medicinal Chemistry, Shanghai Institute of Pharmaceutical Industry, China, 2000

Position: 
Martinos Faculty

Contact

Mailing Address

Building 149, Room 2301
13th Street
Charlestown, MA 02129 USA

General Contact Information

Phone: 
617-643-4886

Additional Information

Biosketch


1. Development of new generations of Amyloid imaging probe. In the past few years, my research has been concentrated on three-phase development of smart NIRF imaging probes for various amyloid beta (A) species. In phase (I), we have effectively developed NIRF probes for insoluble As. In this period, we have invented a brand-new family of NIR fluorescent dyes CRANAD-X, and some of them are smart probes for the insoluble As.
     In recent years, mounting evidence has driven the evolution of the A hypothesis towards the most toxic soluble As. Although several PET imaging probes for insoluble As have been approved by FDA, and a couple of NIR probes for insoluble As have been reported as well, to the best of my knowledge, none of the imaging probes have the potential to reflect the full spectrum of amyloidosis of AD, which spans from over-accumulated soluble As to predominated insoluble As. In our phase (II), we have successfully developed NIR probes for both soluble and insoluble A species, and we believe these probes may have the potential to monitoring the full course of the amyloidosis.
     The initial stage of amyloidosis pathology is represented by excessive accumulation of A monomers and other soluble species, and this early predominance gradually shifts to the majority of insoluble species with the progression of AD. It is clear that, for early molecular pathology detection, selective imaging probes for soluble As are highly desirable. In phase (III), we concentrate our efforts on developing imaging probes for soluble As, thus to accomplish early detecting of AD pathology. Our preliminary data indicates that such probes are achievable.
 
a. Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, Medarova Z, Moore A, Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits. J. Amer. Chem. Soc., 2009,131(42):15257-61. PMCID: PMC278424.
b. 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. PMID: 24116384.
c. Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, and Ran C*, Nearinfrared 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.
d. 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, Available online.

2. Development of two-photon imaging probes. In the last two years, my team has been actively developing multifunctional two-photon imaging probes for A plaques and CAAs (cerebral amyloid angiopathy). We demonstrated that CRANAD-28, a highly bright bifunctional curcumin analogue, could be used for two-photon imaging of A plaques and CAAs in vivo as well as for inhibiting crosslinking of As. Compared to other most used two-photon imaging agents for A plaques, this probe has a longer emission wavelength that enables deeper imaging with a thinned skull. The relative quantum yield of CRANAD-28 was near 100% in ethanol (using Rhodamine B as a reference). In addition, using two-photon imaging, we also showed that PiB-C, a conjugate of Pittsburgh compound B (PiB) and 12-crown-4 ether, could readily penetrate the BBB and efficiently label A plaques and CAAs in an APP-PS1 transgenic mouse.

a. 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.
b. Tian Y, Zhang X, Li Y, Shoup T, Teng X, Elmaleh D, Moore A, Ran C.*, Crown ethers attenuate aggregation of amyloid beta of alzheimers disease. Chem. Commun. 2014, 50(99):15792-5. PMID: 25372154.
c. 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 Alzheimers disease, Proc. Natl. Acad. Sci. USA, 2017, In press.

3. New Strategy for AD Drug Development. In past decades, several categories of A-reducing agents have been developed, and some of them had advanced into clinical trials. Unfortunately, all of these clinical trials, by and large, failed to demonstrate their efficacy and safety. All these failures clearly imply that innovative strategies for developing drugs for AD are urgently needed. We reasoned that crown ethers could be used to neutralize positive charges of the amino groups of As through the formation of hydrogen bonds. We proposed a novel strategy to attenuate the aggregation of As through a non-covalent modification at its surface. Our preliminary results demonstrated that 12-crown-4 and its conjugate PiB-C (PiB is the well known PET ligand for As) could effectively reduce the aggregation of A40, and could rescue the neurotoxicity of A42 in cell studies. 

a. Tian Y, Zhang X, Li Y, Shoup T, Teng X, Elmaleh D, Moore A, Ran C.*, Crown ethers attenuate aggregation of amyloid beta of alzheimers disease. Chem. Commun. 2014, 50(99):15792-5. PMID: 25372154

4. Developing imaging probes and methods for diabetes and obesity. In the past years, one of my research directions has been focused on the development of probes and technologies for Imaging of Metabolically Abnormal Degeneration (MAD) diseases, which include diabetes and obesity.  Based on the structure of streptozotocin (STZ), a beta cell specific small molecule, we have developed two beta-cell specific NIRF probes. More recently, my research has been focused on imaging Brown Adipose Tissue (BAT), which is a re-emerged target for MAD diseases such as diabetes and obesity. However, highly selective imaging probe for BAT mass is still lack. For this project, my primary contributions include: 1) My research group discovered several NIRF probes suitable for imaging BAT mass through a top-down screening method (Manuscript under revision). 2) My group also demonstrated that Cerenkov Luminescence Imaging (CLI), a newly developed technology, could be used to image BAT with 18F-FDG. Compared to PET imaging, CLI is a much cheaper and faster alternative imaging method for brown adipose tissue. I served as the primary investigator for all of these studies.

a. Ran, C., Pantazopoulos, P., Medarova, Z., Moore, A., Synthesis and Testing of Beta-Cell-Specific Streptozotocin-Derived Near-Infrared Imaging Probes, Angew Chemie International Edition, 2007, 46(47), 8998-9001. PMID: 17957665.
b. Zhang X, Kuo C, Moore A, Ran C*, In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging, PLOS One, 2013, 8(4):e62007. PMCID: PMC3634850.
c. 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.
d. Yang J, Yang J, Wang L, Moore A, Liang SH, Ran C*, Synthesis-free PET imaging of brown adipose tissue and TSPO via combination of disulfiram and 64CuCl2, Scientific Reports, 2017, 7(1):8298. PMID:28811616
e. Ran C*, Albrecht DS, Bredella MA, Yang J, Yang J, Liang SH, Cypess AM, Loggia ML, Atassi N,  Moore A, PET imaging of human brown adipose tissue with TSPO tracer 11C-PBR28, Molecular Imaging and Biology, 2017, Accepted.


5. Development of new optical imaging technology. In addition to the contributions described above, my team has also been worked on Cerenkov Luminescence Imaging, which is a newly emerged imaging technology. In our studies, we demonstrated that Cerenkov Luminescence from 18F-FDG could be used as a UV light source to photoactivate caged compounds. The obvious advantage of this technique over traditional external UV irradiation is that Cerenkov luminescence is an internal UV light source and it has no limitation of photoactivation for deep tissues. In addition, we also demonstrated that Cerenkov Luminescence imaging could be a cheaper alternative imaging method for brown adipose tissue, which is a re-emerged target for obesity and diabetes research. I served as the primary investigator for all of these studies.

a. Ran C, Zhang Z, Hooker JM, Moore A, In Vivo Photoactivation Without "Light": Use of Cherenkov Radiation to Overcome the Penetration Limit of Light. Mol Imaging Biol. 2012, 14(2): 156-62. PMID: 21538154.
b. Zhang X, Kuo C, Moore A, Ran C*, In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging, PLOS One, 2013, 8(4):e62007. PMCID: PMC3634850.
c. Zhang X, Kuo C, Moore A, Ran C*, Cerenkov luminescence imaging of interscapular brown adipose tissue. J Vis Exp. 2014 Oct 7;(92):e51790. doi: 10.3791/51790. PMID:25349986.