Person: Weissleder, Ralph
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Weissleder
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Ralph
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Weissleder, Ralph
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Publication Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease(Springer Science and Business Media LLC, 2021-07-14) McAlpine, Cameron; Park, Joseph; Griciuc, Ana; Kim, Eunhee; Choi, Se Hoon; Iwamoto, Yoshiko; Kiss, Máté G.; Christie, Kathleen; Vinegoni, Claudio; Poller, Wolfram; Mindur, John; Chan, Christopher; He, Shun; Janssen, Henrike; Wong, Lai Ping; Downey, Jeffrey; Singh, Sumnima; Anzai, Atsushi; Kahles, Florian; Jorfi, Mehdi; Feruglio, Paulo; Sadreyev, Ruslan; Weissleder, Ralph; Kleinstiver, Benjamin; Nahrendorf, Matthias; Tanzi, Rudolph; Swirski, FilipCommunication within the glial cell ecosystem is essential to neuronal and brain health1–3. The influence of glial cells on β-amyloid (Aβ) and neurofibrillary tau accumulation and clearance in Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) reprograms microglia to ameliorate AD pathology. Upon recognition of Aβ deposits, microglia augment IL-3Rɑ, IL-3’s specific receptor, rendering them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional reprograming of microglia endowing them with an acute immune response program, enhanced motility, and the capacity to cluster and clear Aβ and tau aggregates. These changes restrict AD pathology and cognitive decline. This study identifies IL-3 as a critical mediator of astrocyte-microglia crosstalk and a node for therapeutic intervention in AD.Publication Imaging Cellular Distribution of Bcl Inhibitors Using Small Molecule Drug Conjugates(American Chemical Society, 2014) Giedt, Randy J.; Sprachman, Melissa M.; Yang, Katherine; Weissleder, RalphOverexpression of anti-apoptotic proteins such as Bcl-2 is a cellular mechanism to evade apoptosis; consequently, Bcl-2 inhibitors are being developed as anticancer agents. In this work, we have synthesized a fluorescent version of ABT-199 in an effort to visualize a drug surrogate by high resolution imaging. We show that this fluorescent conjugate has comparable Bcl-2 binding efficacy and cell line potency to the parent compound and can be used as an imaging agent in several cancer cell types. We anticipate that this agent will be a valuable tool for studying the single-cell distribution and pharmacokinetics of ABT-199 as well the broader group of BH3-mimetics.Publication Rapid, high efficiency isolation of pancreatic ß-cells(Nature Publishing Group, 2015) Clardy, Susan M.; Mohan, James F.; Vinegoni, Claudio; Keliher, Edmund J.; Iwamoto, Yoshiko; Benoist, Christophe; Mathis, Diane; Weissleder, RalphThe ability to isolate pure pancreatic ß-cells would greatly aid multiple areas of diabetes research. We developed a fluorescent exendin-4-like neopeptide conjugate for the rapid purification and isolation of functional mouse pancreatic β-cells. By targeting the glucagon-like peptide-1 receptor with the fluorescent conjugate, β-cells could be quickly isolated by flow cytometry and were >99% insulin positive. These studies were confirmed by immunostaining, microscopy and gene expression profiling on isolated cells. Gene expression profiling studies of cytofluorometrically sorted β-cells from 4 and 12 week old NOD mice provided new insights into the genetic programs at play of different stages of type-1 diabetes development. The described isolation method should have broad applicability to the β-cell field.Publication Point-of-Care Technologies for Precision Cardiovascular Care and Clinical Research(Elsevier BV, 2016) King, Kevin Robert; Grazette, Luanda P.; Paltoo, Dina N.; McDevitt, John T.; Sia, Samuel K.; Barrett, Paddy M.; Apple, Fred S.; Gurbel, Paul A.; Weissleder, Ralph; Leeds, Hilary; Iturriaga, Erin J.; Rao, Anupama K.; Adhikari, Bishow; Desvigne-Nickens, Patrice; Galis, Zorina S.; Libby, PeterPoint-of-care technologies (POC or POCT) are enabling innovative cardiovascular diagnostics that promise to improve patient care across diverse clinical settings. The National Heart, Lung, and Blood Institute convened a working group to discuss POCT in cardiovascular medicine. The multidisciplinary working group, which included clinicians, scientists, engineers, device manufacturers, regulatory officials, and program staff, reviewed the state of the POCT field; discussed opportunities for POCT to improve cardiovascular care, realize the promise of precision medicine, and advance the clinical research enterprise; and identified barriers facing translation and integration of POCT with existing clinical systems. A POCT development roadmap emerged to guide multidisciplinary teams of biomarker scientists, technologists, health care providers, and clinical trialists as they: 1) formulate needs assessments; 2) define device design specifications; 3) develop component technologies and integrated systems; 4) perform iterative pilot testing; and 5) conduct rigorous prospective clinical testing to ensure that POCT solutions have substantial effects on cardiovascular care.Publication Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging(Nature Publishing Group, 2017) Cuccarese, Michael F.; Dubach, J. Matthew; Pfirschke, Christina; Engblom, Camilla; Garris, Christopher; Miller, Miles; Pittet, Mikael; Weissleder, RalphInvolvement of the immune system in tumour progression is at the forefront of cancer research. Analysis of the tumour immune microenvironment has yielded a wealth of information on tumour biology, and alterations in some immune subtypes, such as tumour-associated macrophages (TAM), can be strong prognostic indicators. Here, we use optical tissue clearing and a TAM-targeting injectable fluorescent nanoparticle (NP) to examine three-dimensional TAM composition, tumour-to-tumour heterogeneity, response to colony-stimulating factor 1 receptor (CSF-1R) blockade and nanoparticle-based drug delivery in murine pulmonary carcinoma. The method allows for rapid tumour volume assessment and spatial information on TAM infiltration at the cellular level in entire lungs. This method reveals that TAM density was heterogeneous across tumours in the same animal, overall TAM density is different among separate pulmonary tumour models, nanotherapeutic drug delivery correlated with TAM heterogeneity, and successful response to CSF-1R blockade is characterized by enhanced TAM penetration throughout and within tumours.Publication Rapid identification of health care–associated infections with an integrated fluorescence anisotropy system(American Association for the Advancement of Science, 2016) Park, Ki Soo; Huang, Chen-Han; Lee, Kyungheon; Yoo, Yeong-Eun; Castro, Cesar; Weissleder, Ralph; Lee, HakhoHealth care–associated infections (HAIs) and drug-resistant pathogens have become a major health care issue with millions of reported cases every year. Advanced diagnostics would allow clinicians to more quickly determine the most effective treatment, reduce the nonspecific use of broad-spectrum antimicrobials, and facilitate enrollment in new antibiotic treatments. We present a new integrated system, polarization anisotropy diagnostics (PAD), for rapid detection of HAI pathogens. The PAD uses changes of fluorescence anisotropy when detection probes recognize target bacterial nucleic acids. The technology is inherently robust against environmental noise and economically scalable for parallel measurements. The assay is fast (2 hours) and performed on-site in a single-tube format. When applied to clinical samples obtained from interventional procedures, the PAD determined the overall bacterial burden, differentiated HAI bacterial species, and identified drug resistance and virulence status. The PAD system holds promise as a powerful tool for near-patient, rapid HAI testing.Publication PD-L1 is an activation-independent marker of brown adipocytes(Nature Publishing Group UK, 2017) Ingram, Jessica R.; Dougan, Michael; Rashidian, Mohammad; Knoll, Marko; Keliher, Edmund J.; Garrett, Sarah; Garforth, Scott; Blomberg, Olga S.; Espinosa, Camilo; Bhan, Atul; Almo, Steven C.; Weissleder, Ralph; Lodish, Harvey; Dougan, Stephanie; Ploegh, Hidde L.Programmed death ligand 1 (PD-L1) is expressed on a number of immune and cancer cells, where it can downregulate antitumor immune responses. Its expression has been linked to metabolic changes in these cells. Here we develop a radiolabeled camelid single-domain antibody (anti-PD-L1 VHH) to track PD-L1 expression by immuno-positron emission tomography (PET). PET-CT imaging shows a robust and specific PD-L1 signal in brown adipose tissue (BAT). We confirm expression of PD-L1 on brown adipocytes and demonstrate that signal intensity does not change in response to cold exposure or β-adrenergic activation. This is the first robust method of visualizing murine brown fat independent of its activation state.Publication The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes(The Rockefeller University Press, 2017) Anzai, Atsushi; Choi, Jennifer; He, Shun; Fenn, Ashley M.; Nairz, Manfred; Rattik, Sara; McAlpine, Cameron; Mindur, John; Chan, Christopher; Iwamoto, Yoshiko; Tricot, Benoit; Wojtkiewicz, Gregory R.; Weissleder, Ralph; Libby, Peter; Nahrendorf, Matthias; Stone, James; Becher, Burkhard; Swirski, FilipMyocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells. In the heart, fibroblast-derived GM-CSF alerts its neighboring myeloid cells to attract neutrophils and monocytes. The growth factor also reaches the bone marrow, where it stimulates a distinct myeloid-biased progenitor subset. Consequently, hearts of mice deficient in either GM-CSF or its receptor recruit fewer leukocytes and function relatively well, whereas mice producing GM-CSF can succumb from left ventricular rupture, a complication mitigated by anti–GM-CSF therapy. These results identify GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target, bolstering the idea that GM-CSF is a major orchestrator of the leukocyte supply chain during inflammation.Publication Unraveling Tetrazine-Triggered Bioorthogonal Elimination Enables Chemical Tools for Ultrafast Release and Universal Cleavage(American Chemical Society, 2018) Carlson, Jonathan C. T.; Mikula, Hannes; Weissleder, RalphRecent developments in bond cleavage reactions have expanded the scope of bioorthogonal chemistry beyond click ligation and enabled new strategies for probe activation and therapeutic delivery. These applications, however, remain in their infancy, with further innovations needed to achieve the efficiency required for versatile and broadly useful tools in vivo. Among these chemistries, the tetrazine/trans-cyclooctene click-to-release reaction has exemplary kinetics and adaptability but achieves only partial release and is incompletely understood, which has limited its application. Investigating the mechanistic features of this reaction’s performance, we discovered profound pH sensitivity, exploited it with acid-functionalized tetrazines that both enhance and markedly accelerate release, and ultimately uncovered an unexpected dead-end isomer as the reason for poor release. Implementing facile methods to prevent formation of this dead end, we have achieved exceptional efficiency, with essentially complete release across the full scope of physiologic pH, potentiating drug-delivery strategies and expanding the dynamic range of bioorthogonal on/off control.Publication Prediction of Anti-cancer Nanotherapy Efficacy by Imaging(Ivyspring International Publisher, 2017) Miller, Miles; Arlauckas, Sean; Weissleder, RalphAnticancer nanotherapeutics have shown mixed results in clinical trials, raising the questions of whether imaging should be used to i) identify patients with a higher likelihood of nanoparticle accumulation, ii) assess nanotherapeutic efficacy before traditional measures show response, and iii) guide adjuvant treatments to enhance therapeutic nanoparticle (TNP) delivery. Here we review the use of a clinically approved MRI nanoparticle (ferumoxytol, FMX) to predict TNP delivery and efficacy. It is becoming increasingly apparent that nanoparticles used for imaging, despite clearly distinct physicochemical properties, often co-localize with TNP in tumors. This evidence offers the possibility of using FMX as a generic “companion diagnostic” nanoparticle for multiple TNP formulations, thus potentially allowing many of the complex regulatory and cost challenges of other approaches to be avoided.