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Principal Investigator: Richard KP Benninger
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $658,293
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Type 1 diabetes (T1D) results from the destruction of insulin producing β-cells upon immune infiltration and
inflammation of the islets of Langerhans in the pancreas. Prior to T1D onset there is an asymptomatic phase
of many years which presents a window for therapeutic intervention. However, there are limited means for
detecting and tracking the development of insulitis in this ‘pre-symptomatic’ T1D window, to guide and monitor
therapeutic interventions. Ultrasound imaging presents many advantages for clinical deployment, and gas-
filled microbubble (MB) contrast agents are clinically approved, and used in detection and monitoring of a wide
range of diseases. We previously used contrast-enhanced ultrasound to detect signatures of insulitis in pre-
clinical models based on altered pancreas blood flow or inflammation-induced extravasation. While promising,
a key limitation of pancreas imaging in general in T1D is that the islets of Langerhans represent only a few %
of the pancreas volume. Any disease signatures will be ‘diluted’ by background signal, substantially reducing
sensitivity. Thus high-resolution approaches to view the specific disease signatures in T1D are needed.
Ultrasound localization microscopy (ULM) is a super-resolution microvascular imaging technique that provides
microvessel-level spatial resolution noninvasively in vivo, thus potentially enabling the resolution of specific
T1D disease associated changes in the pancreas. Our overall goal is to develop and apply novel ultrasound
contrast agents in combination with ULM and signal processing to detect disease signatures associated with
T1D, to provide image-based guidance and tracking of therapeutic interventions. We will conduct 3 specific
aims: 1): Apply ultrasound localization microscopy to visualize vascular impairments in the pancreas. 2): Map
the distribution of nanodrop accumulation and microvascular leakiness across the pancreas. 3): Apply
molecularly targeted microbubbles and nanodrops to the inflamed and infiltrated islet microenvironment.
Assessing inflammation and immune infiltration in the islet microenvironment using contrast-enhanced
ultrasound imaging represents a fundamentally new paradigm for diagnosing and tracking T1D progression.
The development and application of nanodrop agents and functionalized microbubbles, and use of super-
resolution ULM techniques, represents further innovations which will have broader impact, aiding in diagnosing
both the pace of T1D progression and the efficacy of any preventative treatment prior to clinical onset.
Terms: <Acoustics><Architecture><B9 endocrine pancreas><Beta Cell><Binding><Biodistribution><Blood Vessels><Blood flow><Brittle Diabetes Mellitus><CD62L Antigens><Cell Communication and Signaling><Cell Signaling><Cell surface><Chronic><Clinic><Clinical><Complement Activation><Complications of Diabetes Mellitus><Contrast Agent><Contrast Drugs><Contrast Media><Detection><Development><Diabetes Complications><Diabetes-Related Complications><Diabetic Complications><Diagnosis><Diameter><Disease><Disorder><Drops><Echography><Echotomography><Endocrine Pancreas><Endothelial Cells><Engineering / Architecture><Functional Imaging><Gases><Goals><Histologic><Histologically><Humulin R><Hypoglycemia><IDDM><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune infiltrates><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Impairment><In Vitro><Individual><Infiltration><Inflammation><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Intracellular Communication and Signaling><Investigation><Ionizing Electromagnetic Radiation><Ionizing radiation><Islands of Langerhans><Islets of Langerhans><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><L-Selectin><LAM-1><LAM-1 Leukocyte Adhesion Molecule><LECAM-1><Leu-8 Antigen><Ligands><Lymphocyte Adhesion Molecule 1><Maps><Measurement><Medical Ultrasound><Mel-14 Antigen><Microbubbles><Microscopy><Microvascular Permeability><Molecular Interaction><Molecular Target><Monitor><Nesidioblasts><Novolin R><Outcome><Pancreas><Pancreatic><Pancreatic Islets><Pars endocrina pancreatis><Patients><Peptides><Perfusion><Phase><Physiologic Imaging><Pre-Clinical Model><Preclinical Models><Preventative treatment><Preventive treatment><Radiation><Radiation-Ionizing Total><Radiopaque Media><Recommendation><Regular Insulin><Resolution><Risk><Route><Sensitivity and Specificity><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Sudden-Onset Diabetes Mellitus><Surface><T1 DM><T1 diabetes><T1D><T1DM><TQ1 Antigen><Techniques><Text><Therapeutic Intervention><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><biological signal transduction><blood glucose regulation><clinical imaging><complement pathway regulation><contrast enhanced><contrast imaging><developmental><diagnostic ultrasound><glucose control><glucose homeostasis><glucose regulation><human subject><hypoglycemic><hypoglycemic episodes><image-based method><imaging><imaging method><imaging modality><immune cell infiltrate><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vivo><in vivo Model><inflammation marker><inflammatory marker><innovate><innovation><innovative><insulin dependent diabetes><insulin dependent diabetes mellitus onset><insulin dependent type 1><insulitis><intervention therapy><ionizing output><islet><islet progenitor><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><meter><mouse model><murine model><nano><novel><pancreas imaging><physiological imaging><public health relevance><resolutions><response><signal processing><sonogram><sonography><sound measurement><structural imaging><success><super high resolution><superresolution><type 1 diabetes onset><type I diabetes><type one diabetes><ultra high resolution><ultrasound><ultrasound imaging><ultrasound scanning><vaporization><vascular><β-cell><β-cells><βCell>