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PET-RTRC

Projects

Technology Research & Development (TR&D)

The goal of each TR&D project is to develop new PET radiotracers that will image biologic targets modulating the ubiquitous disease processes of inflammation and oxidative stress.

  • Translating S1P1 ligand 11C-TZ3321 into initial human evaluations for safety and efficacy
  • Completing in vivo characterization of 18F-labeled new and selective tracer pharmaceutical properties in inflammatory diseases animal models

Co-leaders: Zhude Tu, PhD, and Robyn S. Klein, MD, PhD

Applications: Multiple sclerosis, atherosclerosis, acute and chronic liver and lung injury, diabetes, cancer, rheumatoid arthritis, inflammatory bowel disease and others

  • Translating a C-C chemokine receptor type 2 (CCR2) targeted PET radiotracer using a peptide ECL1 inverso (64Cu-DOTA-ECL1i) to monitor the CCR2+ pro-inflammatory macrophage subsets in inflammatory diseases and cancers
  • Developing next generation CCR2 targeted radiotracers to image the pro-inflammatory macrophage subset
  • Developing a scavenger receptor CD163 targeted PET probe to image the tissue-resident anti-inflammatory macrophage subset
  • Tracking the dynamic temporal-spatial distribution of macrophage subsets in vivo along the progression and regression of inflammatory diseases and malignancies using PET

Co-leaders: Yongjian Liu, PhD, and Robert J. Gropler, MD

Applications: Atherosclerosis, Alzheimer’s disease, inflammatory lung disease and numerous cancers

  • Design, synthesize and validate gallium-68 incorporated PET tracers for imaging ROS-mediated oxidative stress and MPO-driven activity

Co-leaders: Vijay Sharma, PhD, and Andrew Gelman, PhD

Applications: Prostate cancer, cardiac dysfunction, Parkinson’s disease and pulmonary diseases

Results

Inflammatory monocytes and macrophages in the heart express C-C chemokine receptor 2 (CCR2) on their cell surface and contribute to heart failure pathogenesis. This study established the feasibility of imaging CCR2+ cells by positron emission tomography in patients with myocardial infarction.

Abstract

Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor type 2 (CCR2) is specifically expressed on inflammatory populations of monocytes and macrophages that contribute to the development and progression of heart failure. Here, we evaluated a peptide-based imaging probe (64Cu-DOTA-ECL1i) that specifically recognizes CCR2+ monocytes and macrophages for human cardiac imaging. Compared to healthy controls, 64Cu-DOTA-ECL1i heart uptake was increased in individuals after acute myocardial infarction, predominately localized within the infarct area, and was associated with impaired myocardial wall motion. These findings establish the feasibility of molecular imaging of CCR2 expression to visualize inflammatory monocytes and macrophages in the injured human heart.

CCR2 imaging in control individuals and patients with myocardial infarction.

Representative 99mTc-tetrofosmin single-photon emission computed tomography/computed tomography (SPECT–CT) and differential 64Cu-DOTA-ECL1i (CCR2) PET–CT images of healthy controls and patients after STEMI. 99mTc SPECT–CT perfusion and CCR2 PET–CT images are co-registered and comparative anatomic slices are shown. 99mTc SPECT–CT measures myocardial perfusion, which identified the infarct location (areas of reduced perfusion). CCR2 uptake is evident within and surrounding the infarct region and not in controls. Differential 64Cu-DOTA-ECL1i images are corrected for blood activity. Green and red arrowheads denote the infarct region. Color scale bar indicates normalized uptake of relative tracer.

Lavine, K.J., Sultan, D., Luehmann, H. et al. Nat Cardiovasc Res 2, 874–880 (2023)

Visualizing inflammatory monocytes and macrophages in the human heart. Nat Cardiovasc Res 2, 869–870 (2023)

This article describes the development of CD163-targeted PET radiotracer, 64Cu-ICT-01. CD163 expression is associated with the vulnerability of human carotid plaques. The targeted imaging using 64Cu-ICT-01 PET/CT may provide new insights into the role of CD163+ macrophage in the pathogenesis of atherosclerosis and be a useful tool to risk stratify patients for appropriate management.

Abstract

Purpose: Tissue resident macrophages are complementary to proinflammatory macrophages to promote the progression of atherosclerosis. The non-invasive detection of their presence and dynamic variation will be important to understand their role in the pathogenesis of atherosclerosis. The goal of this study was to develop a targeted PET radiotracer for imaging CD163+ macrophages in multiple mouse atherosclerosis models and assess the potential of CD163 as a biomarker for atherosclerosis in humans.

Methods: CD163 binding peptide was identified using phage display and conjugated with NODAGA chelator for 64Cu radiolabeling (64Cu-ICT-01). CD163 overexpressing U87 cells were used to measure the binding affinity of 64Cu-ICT-01. Biodistribution studies were performed in wild type C57BL/6 mice at multiple time points post tail vein injection. The sensitivity and specificity of 64Cu-ICT-01 imaging CD163+ macrophages upregulated on the surface of atherosclerotic plaques were assessed in multiple mouse atherosclerosis models. Immunostaining, flow cytometry, and single cell RNA sequencing (scRNAseq) were performed to characterize the expression of CD163 on tissue resident macrophages. Human carotid atherosclerotic plaques were used to measure the expression of CD163+ resident macrophages and test the binding specificity of 64Cu-ICT-01.

Results: 64Cu-ICT-01 showed high binding affinity to U87 cells. Biodistribution study showed rapid blood and renal clearance with low retention in all major organs at 1 h, 2 h, and 4 h post injection. In an ApoE-/- mouse model, 64Cu-ICT-01 demonstrated sensitive and specific detection of CD163+ macrophages and capability to track the progression of atherosclerotic lesions, which was further confirmed in Ldlr-/- and PCSK9 mouse models. Immunostaining showed elevated expression of CD163+ macrophages across the plaques. Flow cytometry and scRNAseq confirmed the specific expression of CD163 on tissue resident macrophages. Human tissue characterization demonstrated high expression of CD163+ macrophages on atherosclerotic lesions and ex vivo autoradiography revealed specific binding of 64Cu-ICT-01 to human CD163.

Conclusion: This work reported the development of a PET radiotracer binding CD163+ macrophages. The elevated expression of CD163+ resident macrophages on human plaques indicated the potential of CD163 as a biomarker for vulnerable plaques. The sensitivity and specificity of 64Cu-ICT-01 imaging CD163+ macrophages warrant further investigation in translational settings.

Zhang, X., Heo, G.S., Li, A. et al. J Nucl Med, submitted

Collaborative Projects (CP)

Collaborative Projects (CPs) work in conjunction with TR&Ds, expediting the translational timeline through comprehensive preclinical evaluation of the radiotracers in development.

To propose a project, please complete the Collaborative Projects Application.

Project: TR&D 1, TR&D 2
Location: WUSM; Department of Medicine
Funding: R35NS122310, 5/1/2021-4/30/2029
Publications
Description: This Research Program Project will define new concepts in the molecular neuroimmunological regulation of synapses, mononuclear cell and glial interactions, inform studies of related processes throughout the nervous systems, and will likely enhance our understanding of autoimmune, neurodegenerative, infectious and other disorders of memory. Published studies have inspired this Program to explore the role of sphingosine-1-phosphate receptor 2 (S1PR2) signaling in the meninges of a mouse model of Multiple  Sclerosis as well as CCR2 upregulation on CNS infiltrating mononuclear cells during neuroinflammation, which makes targeting these 2 receptors of great interest to this research program.

Project: TR&D 1
Location: University of North Carolina-Chapel Hill, Department of Radiology
Funding: 5R01EB029451, 5/1/2020-1/31/2024
Publications
Description: This grant focuses on development of efficient radiosynthetic methods of radiolabeleing inactivated arene molecules including S1P1 molecules. Concomitantly, the PI inspired by S1P2 signaling in bladder cancer and other cancers, is exploring of S1P1/2 bladder cancer radiotherapeutic agents.

Project: TR&D 1, TR&D 2
Location: Stanford University;  Rad/Molecular Imaging Program
Funding: R01NS114220, 7/15/2020-4/30/2025
Publications
Description: B lymphocytes play a complex and critical role in Multiple Sclerosis (MS) pathology and are the target of several therapeutics in clinical trials. While monoclonal antibodies targeting the B cell surface marker CD20 (i.e. Rituximab, Ocrelizumab) dramatically reduce the annualized relapse rate and delay disability progression, not all patients respond, likely due to the heterogenous nature of MS. The project will focus on development and evaluation of a novel immuno-PET radiotracers based on clinically approved CD19 and CD20 monoclonal antibody therapeutics. The roles of S1PR1/2 and CCR2+ radiotracers will provide more integrated readouts of innate and adaptive immunity responses and will allow this Program to more accurately position B-cell activity within an immune response.             

Project: TR&D 2
Location: WUSM; Center for Cardiovascular Research
Funding: 1R35HL161185, 1/1/2022-12/31/2028
Publications
Description: This research program is seeking to unravel and leverage unrecognized complexities within the innate immune system to abrogate heart failure pathogenesis, potentiate functional recovery of the failing heart, and prevent heart transplant rejection. Specifically being studied are the relative contributions and interrelationship of pro-inflammatory macrophages and resident macrophages in the promotion and resolution of inflammation, as well as the remodeling process.

Project: TR&D 2
Location: Proteogenomics Research Institute- University of Alabama at Birmingham
Funding: P01CA221775-04, 7/8/2019-6/30/2024
Publications
Description: This project will produce 89Zr-hAnnA1 for imaging studies in both preclinical and a first-in-human clinical trial to enable key insights into the pharmacokinetics and biodistribution of the humanized form of our Annexin A1 (ANXA1) targeting antibody (hAnnA1). It is known that ANXA1 has long been classed as an anti-inflammatory protein due to its control over leukocyte-mediated immune responses. However, it is now recognized that ANXA1 has widespread effects beyond the immune system with implications in maintaining the homeostatic environment within the entire body due to its ability to affect cellular signaling, hormonal secretion, fetal development, the aging process and development of disease. In the studies using the radiotracers developed within the TR&D 2, it was determined the dynamic variation of macrophage subsets (CCR2+ M1 pro-inflammatory macrophages, CD163+ M2 anti-inflammatory macrophages) during inflammation and malignancies processes. Thus, it is interesting to integrate ANXA1 imaging with CCR2 and CD163 PET to better understand ANXA1’s effect on immune cells trafficking.

Project: TR&D 2
Location: Yale University, Department of ;
WUSM, Department of Radiology
Funding: R01 AG065917, 8/1/2020-3/31/2025
Publications
Description: The central objective of this proposal is to clinically translate 64Cu-RYM2, a radiotracer of tissue MMP activity, for first in human PET/CT studies of AAA, hypothesizing that the approach can detect AAA MMP activity. In this grant Yale is evaluating 64Cu-RYM2 binding to human AAA tissue and its correlates in relation to tissue MMP activity and addressing 64Cu-RYM2 pharmacokinetics and imaging performance in murine AAA models. WUSM is performing the necessary studies to translate 64Cu-RYM2 for human AAA imaging. In AAA, the MCP-1/CCR2 axis is important for monocyte recruitment to the aortic wall where their secretion of MMPs leads to elastolysis.

Project: TR&D 2
Location: Stanford University;  Rad/Molecular Imaging Program
Funding: R01CA250557, 2/1/2021-1/31/2026
Publications
Description: Modulation of immune cells (i.e. macrophages) within the tumor microenvironment (TME) has great potential to overcome the immunosuppressive TME and enhance treatment outcome in combination therapy. It is known that macrophages subsets are the major components for the TME and contributor to the immunosuppressive environment affecting the effective immunotherapy. Therefore, it will be useful to determine the level of macrophage subsets within the TME of PDAC tumors and the variation during tumor progression and following treatment. The information collected from the PET imaging studies will help us to better understand the immune cells profile within the TME to further increase treatment efficiency. The CCR2 tracers targeting proinflammatory macrophages (CCR2+) and CD163 tracers targeting tumor-associated macrophages (CD163+) could provide critical information about macrophages influx in PDAC tumors for optimal therapeutic efficacy.       .

Project: TR&D 3
Location: Louisiana State University- Shreveport
Funding: R01HL149264, 7/1/2020-6/30/2024
Publications
Description: The primary goal of the R01 award is to gain mechanistic insights into findings regarding redox regulation, reactive oxygen species (ROS), and their impact on angiogenesis, arteriogenesis, and tissue responses during ischemia through examining the hypothesis that endothelial cell and monocyte Cystathionine y-lysase (CSE) dependent sulfide formation differentially regulate ischemic vascular remodeling, NO bioavailability, and redox stress. The availability of the TR&D’s agents, such as Galuminox, will enhance the understanding of mechanism(s) of redox species mediating ischemic vascular remodeling.

Project: TR&D 3
Location: Barrow Neurological Institue- Phoenix
Funding: TA-1805-31003, 7/1/2020-6/30/2024
Publications
Description: Myeloid-derived suppressor cells (MDSCs) can suppress T cell activities in the central nervous system (CNS) and the meninges and modulate the clinical course and pathology of the main multiple sclerosis (MS) animal model, the experimental autoimmune encephalomyelitis (EAE). This proposal seeks to study MDSCs immune-modulatory functions, regulated by MiR-223, in the context of MS in the EAE animal model. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). TR&D 3 agents will provide useful in vivo tools to enhance understanding of the mechanism (s) responsible for the ROS-mediated MDSC-induced immune suppression and help calibrate MiR-223 as disease modifying intervention.

Project: TR&D 3
Location: Yale University; Section of Cardiovascular Medicine
Funding: R01HL159459, 8/26/2021-7/31/2025
Publications
Description: Acute respiratory distress syndrome (ARDS) results in permeability of endothelial cells, wherein vascular microvessels are postulated to lose their junctional integrity, show increased myosin contractions promoting migration of polymorphonuclear leukocytes and infiltration of solutes and fluids into the alveolar lumen (pulmonary edema). Most of these physiological alterations are accompanied by oxidative imbalance and deviations from normal mitochondrial function. This award aims to test the hypothesis that during symptomatic clinical expression of ARDS, whether activation of matrix metalloproteinase (MMP) can be visualized, quantified (with SPECT), and more importantly successfully inhibited with a localized therapeutic delivery approach to mitigate ARDS progression and vascular and myocardial injury.

Project: TR&D 2
Location: Emory University; Winship Cancer Institute
Funding: R01 EB029320, 8/15/2020-4/30/2024
Publications
Description: The aims of this project are focused on addressing the unmet clinical need of diagnosing bacterial infections, such as heart valve infections (endocarditis), bone infections (osteomyelitis), and abscesses, at an early stage in a specific and sensitive manner. The current diagnostic methods rely on clinical judgment, non-specific imaging techniques (e.g., CT, MRI, white blood cell scans), and cultures, which either provide indirect information or take several days for results. The central objective of this award is to develop the next generation of maltodextrin-based PET contrast agents that can effectively image and diagnose early-stage gram-positive and gram-negative infections.   

Project: TR&D 1, TR&D 3
Location: WUSM; Department of Radiology
Funding: R01 NS107281, 6/1/2019-5/31/2024
Publications
Description: Parkinson disease (PD) causes motor and non-motor manifestations. Underlying pathology includes abnormal deposition of α-synuclein lower brainstem (and a few higher cortical areas) and then spreads to more up the brainstem and higher cortex. Initial motor symptoms likely reflect loss of nigrostriatal dopamine containing nerves but cortical dysfunction may contribute to motor and non-motor problems that frequently develop in PD. Direct α-synuclein involvement, neurotransmitter deficiencies or functional changes in brain networks may contribute to cortical dysfunction. Currently, no treatment delays the relentless progression of PD. This proposal addresses three specific issues. This award aims to investigate a new mechanism that could lead to cortical dysfunction, validate neuroimaging biomarkers of this process and determine whether these imaging biomarkers can serve as a measure of target engagement for a new drug synoxizyme (previously called carboxyfullerene or C3) that we have shown can restore nigrostriatal dopaminergic function after injury with the selective neurotoxin, MPTP.

Project: TR&D 3
Location: Memorial Sloan Kettering Cancer Center; The Radiochemistry and Molecular Imaging Probe (RMIP) Core Facility
Funding: R35CA232130, 9/4/2019-8/31/2026
Publications
Description: This R25 award plans to focus on three main areas of discovery: (1) Can our successful imaging agents be transformed into theranostic agents with the ability to quantify the target through non-invasive imaging while providing concomitant lethality? (2) How can our theranostic agents be optimally deployed to quantitatively and non-invasively interrogate and treat tumor heterogeneity? (3) Following conventional and/or novel targeted therapies, can we image cancer-specific pathways to provide immediate and real-time predictors of response? We will exploit recent findings and novel methods to answer these questions, using an integrated set of imaging, chemical, genomic and cancer biology approaches.

Project: TR&D 2
Location: WUSM; Department of Surgery
Funding: R01 HL153436, 8/1/2020-7/31/2024
Publications
Description: Abstract Abdominal aortic aneurysm (AAA) represents a life-threatening degenerative vascular disease. AAAs usually remain asymptomatic until they rupture, leading to high mortality. The clinical imaging of AAAs largely centers around measurement of AAA diameter, which is a poor marker for rupture prediction. There is an unmet clinical need for a molecular imaging strategy to phenotype AAA patients for risk stratification. This project addresses the absence of a reliable diagnostic modality and medical therapy to prevent abdominal aortic aneurysm (AAA) growth and rupture in patients, leading to high mortality in those over the age of 65 years- old. Due to the pathogenic role of the monocyte chemoattractant protein-1 / C-C chemokine receptor type 2 (MCP-1/CCR2) axis in AAA, this award will study the ability of 64Cu-DOTA-ECL1i PET/CT to predict the murine AAA rupture and serve as a companion diagnostic to assess CCR2 molecular therapy of murine AAA. We will perform the first-in-patient evaluation of 64Cu-DOTA-ECL1i PET/CT to image and detect AAA inflammation in a preoperative setting and acquire key biological information from AAA specimens collected at the time of open AAA repair, in order to assess the potential of 64Cu-DOTA-ECL1i PET in the management of AAA patients.

Service Projects (SP)

Service Projects (SP) gain access to mature center products otherwise unavailable, providing an opportunity for the advancement of research and newly formed collaborations. 

To participate, please complete the Service Project Application.

Project: TR&D 1
Location: Yale University
Funding: P30 DA046345 (sub), 8/15/2019-6/30/2024
Publications
Description: Brain immune mechanisms are heavily implicated in opioid use disorder (OUD), a major public health concern. There is a need to develop novel PET radiotracers that target diverse immune mechanisms to improve basic science understanding in the context of OUD. As part of the PET Addiction Centers of Excellence (PACE) project, we are characterizing the imaging properties of novel PET radiotracers that target Reactive Oxygen Species (ROS), which are associated with tissue damage, and the Sphingosine 1 Phosphate Receptor 1 (S1PR­1), which is associated with regulating responses to brain immune stimuli, and is generally neuroprotective. The goal is to validate the imaging properties and sensitivity to OUD-relevant immune challenges in preclinical models anticipating translation to human use.

Project: TR&D 1
Location: WUSM
Funding: K99/R00 -AI159380, 8/8/2022-7/31/2026
Publications
Description: This award aims to use innovative noninvasive PET and MR methods to provide ways to investigate the relationships between innate and adaptive immune responses and glutamate dynamics in pre-clinical multiple sclerosis (MS) models. The encouraging outcome of the initial PET study in mouse model of MS assists the PI seeking addition funding to further explore the potential of the S1PR1 proteins as a biomarker for MS and inflammatory response of other diseases.

Project: TR&D 1
Location: Howard University; Department of Radiology
Funding: R01NS123442-01A1, 5/1/2022-4/30/2027
Publications
Description: Traumatic brain injury (TBI) is one of the leading causes of death and disability in the United States. Health disparities exist among African Americans with a 35% higher TBI incidence compared to Caucasians, but are less likely to have appropriate follow-up monitoring after emergency department discharge. TBI accelerates the development of neurodegenerative diseases, including Alzheimer’s and psychiatric conditions such as depression. This project combines high-resolution glucoCEST and the Dynamic Contrast Enhanced perfusion MRI for concomitant cerebral blood flow measurements to identify the neurovascular coupling state following TBI over time. This SP will explore the role S1PR1 in the development of neuroinflammation in a pre-clinical TBI model by quantifying the S1PR1 expression change by both ex vivo gene expression and in vivo small animal PET/CT measurements and investigating the relationship of the neuroinflammation, microglial activation, and glucose metabolism (using FDG) and diffusion MRI following diffuse axonal injury.

Project: TR&D 1
Location: University of Southern California; Keck School of Medicine
Funding: R21CA258019, 5/13/2021-4/30/2024
Publications
Description: This project plans to develop 18F-labeled bisphosphonate (BP) PET radiotracers for the early detection of myeloma bone disease (MBD), which is characterized by the presence of lytic lesions and associated with severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia. In this project, both 18F-BP and the [18F]S1P1 tracer will be used to image mice with multiple myeloma. Immunohistochemical and autoradiography studies will be performed to measure the S1PR2 expression. A relationship between tumor uptake of 18F-BP and [18F]S1P1 tracer will be investigated. Tumor targeting efficacy of other new promising S1PR2 radiotracers will also be studied.

Project: TR&D 2
Location: University of Pittsburgh Medical Center
Funding: K08 HL144911, 7/17/2019-7/1/2024
Publications
Description: The objective of this SP is to characterize the immuno-metabolic heterogeneity of macrophages in atherosclerosis and correlates with histological indices of plaque vulnerability. This effort is based on the recent ex vivo observations that whereas increased glucose metabolism reflects a pro-inflammatory macrophage phenotype enhanced glutamine and acetate utilization associated with macrophage subsets supporting inflammation resolution.

Project: TR&D 2
Location: WUSM; Department of Internal Medicine- Division of Pulmonary & Critical Care Medicine
Funding: 1R01HL151685-01A1, 2/5/2021-12/31/2025
Publications
Description: The goals of this project are to complete CCR2 PET imaging to evaluate modulation of CCR2+-specific inflammation during the course of fibrotic lung disease in animal models, validate the detection of CCR2 cells in human lung tissue, and assess the potential for monitoring patients. It will also study patients with Idiopathic Pulmonary Fibrosis (IPF) and other fibrotic lung diseases, assess the relationship between PET uptake, CT imaging, and clinical status, then validate the relationship of PET uptake with CCR2-mediated inflammation, lung texture analysis, and pro-fibrotic gene expression in lungs removed after transplant. The results generated from this study will help to improve the understanding of the role of CCR2+ cells in the pathogenesis of pulmonary fibrosis.

Project: TR&D 2
Location: University of Utah; Departments of Radiology and Biomedical Informatics
Funding: R01 HL 159200, 9/1/2021-8/31/2026
Publications
Description: The goal of this project is to develop and test at multiple centers a highly efficient and easily used MRI technique for the analysis and management of cervical carotid disease. They aim to accomplish this using multi- parametric non-contrast MRI sequences coupled with the latest high signal to noise ratio (SNR) neck-shape- specific (NSS) RF coils and innovative machine learning (deep neural network) analysis methods. By utilizing 64Cu-DOTA-ECL1i, this project will have the capability to non-invasively track CCR2+ cells in humans via PET imaging and correlate with their findings using MR imaging such as plaque burden change and the development of intraplaque hemorrhage to better understand atherosclerosis biology. Moreover, the SP will be able to determine whether the co-localized biologic and anatomic information requires PET/MR or can be obtained with PET/CT.

Project: TR&D 3
Location: WUSM; Department of Radiology
Funding: R01AG046927, 3/1/2019-2/29/2024
Publications
Description: Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, and obesity is generally considered to be the primary preventable risk factor for OA. The overall objective of this project is to examine the influence of dietary fatty acids in obesity-induced OA and to examine their interaction with altered biomechanical and pro-inflammatory factors using various in vitro and in vivo rodent models. Because oxidative stress is a critical initiator of chronic inflammation in OA, PET with [68Ga]Galuminox will allow them to ascertain those s in vivo, as well as the ability of various anti-inflammatory therapies in correcting inflammation and preventing joint disease.

Project: TR&D 3
Location: Massachussetts General Hospital- Harvard Medical School
Funding: P41EB022544, 9/30/2017-4/30/2027
Publications
Description: The aims of the CMITT are to develop several powerful MR technologies to enhance PET/MR for physiological imaging, develop an innovative physics-informed AI-based pipeline of data processing in PET/MR, and develop radiotracers and PET/MR imaging methods for measuring cellular membrane potential in the myocardium and mitochondrial membrane potential outside the heart, demyelination in the brain, and immune function throughout the body.

Project: TR&D 3
Location: University of California- San Diego; University of Michigan
Funding: R01CA238042, 3/1/2019-2/29/2024
Publications
Description: Most cancers would not be fatal if they did not spread (metastasize); the greatest damage is caused by a few tumorigenic cells have the potential to metastasize, i.e., they can escape the tumor environment, enter blood stream, evade the immune system and chemotherapy drugs, seed elsewhere in the body and successfully nucleate a metastatic tumor; finding those most sinister cells before they have spread has been an unrealized goal. This grant seeks to develop, synthesize, select, optimize, and validate novel fluorescent biosensors/ probes to detect and measure the ‘potential’ for metastasis of single living cancer cells. They are evaluating the metastatic potential of single cell imaging of GIV activation in breast cancer using patient- derived xenografts. Initial studies in cell-based assays indicate that GIV translocates to mitochondria, regulating mitochondrial dynamics and production of ROS.

Project: TR&D 1
Location: University of Texas- Southwestern; Department of Radiology
Funding: Institutional, 4/1/2022-3/30/2027
Publications
Description: The goal of this project is to develop multimodality imaging methods to noninvasively and longitudinally monitor drug delivery and treatment efficacy.

Project: TR&D 1
Location: WUSM
Funding: Institutional KLS, 2022-2024
Publications
Description: This project uses magnetic resonance imaging (MRI) and positron emission tomography (PET) to study the pathological drivers of tissue damage and disability in MS. They are interested in understanding how unrecognized or under-treated aspects of MS pathophysiology contribute to symptoms, clinical worsening, and neurodegeneration in patients with MS. The goal is to further understand how MS exerts its pathological influence on the brain and spine in hopes of identifying novel therapeutic avenues for patients living with MS.

Project: TR&D 2
Location: Hannover Medical School
Funding: Leducq Foundation, 1/1/2021-12/31/2025
Publications
Description: Inflammation and fibrosis represent cardinal hallmarks of myocardial remodeling and heart failure progression. Despite a wealth of data documenting robust clinical associations, proof of concept causation, and putative disease mechanisms, it has remained challenging to effectively target inflammation and fibrosis in the human heart. Until recently, the exact cell types that mediate these important pathological processes were not well defined. Members of this network have identified an inflammatory-fibrosis axis comprised of chemokine C–C motif receptor-2 (CCR2) expressing monocytes and macrophages and activated fibroblasts expressing fibroblast activation protein (FAP) that are essential for the development and progression of heart failure in animal models. The overarching goals of this network are: 1) Establish the molecular basis by which myocardial inflammation orchestrates key elements of adverse left ventricular (LV) remodeling including myocardial fibrosis, translate molecular imaging strategies that will visualize mechanistic elements relevant in both pre-clinical disease models and humans, and develop therapeutic approaches that limit and/or reverse pathological cardiac fibrosis; 2) Accelerate scientific breakthroughs and innovation through team science engendered by the network and; 3) Generate multi-disciplinary training programs in cardioimmunology to train the next generation of scientists We believe that these mechanistic and translational studies will identify new opportunities to improve the longevity and health of patients with LV remodeling and heart failure.

Project: TR&D 2
Location: Saint Louis University; Department of Pharmacology and Physiology
Funding: Institutional CTRFP, 3/1/2022-2/28/2023
Publications
Description: This study will assess myocardial inflammation in individuals with dysfunctional lipid metabolism using a novel non-invasive positron emission tomography (PET) imaging approach in patients with reduced or absent levels of CD36.

Project: TR&D 2
Location: Ichan School of Medicine at Mount Sinai
Funding: Institutional, Through 2023
Publications
Description: This research focusses on the development and implementation of multiparametric imaging readouts to non-invasively study immune responses in cardiovascular disease and beyond.

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