TR&D and Collaborative Projects

The Hyperpolarized MRI Technology Resource Center is based on 3 Technology Research & Development (TR&D) projects and its development is driven in a push-pull manner by the Collaborative Projects.  Below are information on each of the TR&D projects and a summary of the current Collaborative Projects. 

 

The Hyperpolarized MRI Technology Resource Center  Research & Development

TR&D Project 1: Development of Improved DNP Methodology and HP MR Acquisition Techniques

Daniel B. Vigneron, PhD
TR&D1 Project Leader
dan.vigneron@ucsf.edu
(415) 476-3343

 

Peder Larson, PhD
TR&D1 Project Leader
peder.larson@ucsf.edu
(415) 514-4876

 

Hyperpolarized MRI using Dynamic Nuclear Polarization (DNP) is a powerful new imaging technique that uses specialized instrumentation to provide MR signal enhancement of 10,000-100,000 fold for 13C labeled compounds. To advance current hyperpolarized carbon-13 methodology, major advances in Dynamic Nuclear Polarization (DNP) instrumentation/methods and MR acquisition techniques are required to increase the applicability, reliability and information content of this emerging imaging technology.

This Technology Resource & Development (TR&D1) project is carried out by a multidisciplinary team with extensive expertise in basic NMR science, mechanical, electrical and instrumentation design, bioengineering, and DNP physics and engineering. In addition to this expertise, we have extensive facilities including mechanical and electronics shops, multiple NMR systems, MR scanners, and research DNP polarizers.

In conjunction with the Collaborative Project investigators and driven by the needs of their research projects, this Technology Research and Development (TR&D1) project: 1) develops and tests new DNP polarizer hardware and techniques to produce higher, more robust liquid state polarizations that benefits all Collaborative projects, 2) enables reliable multi-compound polarizations for TR&D2 and the Collaborative projects, and 3) develops robust MR acquisition techniques tailored to anatomic location, animal model, hyperpolarized molecule(s) and approach for all Collaborative Projects. The methods developed are disseminated to the Service Project investigators and to the broader HP research community via web documents and downloads on the website.

TR&D Project 2: Development of Novel Hyperpolarized MR Molecular Imaging Probes, Realistic Pre-Clinical Models and Correlative Science Methods

John Kurhanewicz, PhD
TR&D2 Project Leader
john.kurhanewicz@ucsf.edu
(415) 514-9711


The peer-reviewed and funded Collaborative Projects and the Service Projects from leading hyperpolarized MR sites are the scientific driving forces behind HMTRC developments which address the need for improved hyperpolarized (HP) probes and techniques, and more realistic pre-clinical models of human disease. In this TR&D project we take advantage of our extensive experience in combining hyperpolarized MR techniques with novel NMR-compatible bioreactors to develop and provide improved pre-clinical models for hyperpolarized MR probe testing. This TR&D project also builds on our extensive experience with HP MR probe development and optimization, and the unique HP MR environment at UCSF.

In specific aim 1, we aim to greatly improve hyperpolarized probe preparations and hyperpolarized methods with an emphasis on increased sensitivity, robustness, cost-effectiveness, ease of dissemination, and translatability. Also we will investigate novel HP probes to address new questions raised by the collaborative projects. As part of specific aim 2, novel 10 and 5 mm MRI and PET compatible 3D cell and tissue culture bioreactors have been micro-engineered, robustly and cost-effectively produced, and extensively tested and validated in cell and tissue culture studies performed in the collaborative and service projects. Driven by the needs of these projects, we now propose future bioreactor designs incorporating new biologic measurement capabilities, addition of novel cell culture constructs, development of a bioreactor power-injector for improved probe and drug delivery, development of a micro-bioreactor system capable of studying a single biopsy sample, and extension of human cell & tissue bioreactor studies to novel murine models. TR&D2 has also made substantial progress developing and implementing procedures to provide correlative pathologic, biologic and imaging data critical for understanding and validating HP MR findings in the collaborative projects. As requested by both our external advisory board and the new needs of these projects, these biomarker validation studies will be augmented by the addition of new metabolomics assays, enzyme activity staining assays, and PET/HP MR correlative studies.

Since the ultimate goal of this TR&D project is the dissemination of the research findings to the biomedical community, we have disseminated the bioreactor technology and optimized hyperpolarized preparations, hyperpolarization methods, correlative biology and methods through publications on the HMTRC website, interactions at scientific meetings, biennial symposiums, and hands-on training.

TR&D Project 3: Open-Source Tools for Processing Hyperpolarized MR Data

Sarah J. Nelson, PhD
TR&D3 Project Leader
sarah.nelson@ucsf.edu
(415) 476-6383

 

Duan Xu, PhD
TR&D3 Project Leader
duan.xu@ucsf.edu
(415) 514-4455

 

Jason Crane, PhD
TR&D3 Project Leader
jason.crane@ucsf.edu
(415) 514-4426

 

The goal of this TR&D project is to develop novel, open-source, DICOM compliant, cross-platform software tools for reconstruction, quantification and visualization of hyperpolarized MR data as driven by the needs of the Collaborative Projects. There are currently no other packages available for analysis of the results obtained using the fast imaging and spectroscopy pulse sequences associated with this new in vivo technology. This address a pressing need because the multi-dimensional data produced following injection of pre-polarized imaging probes provide dramatic improvements in sensitivity over conventional methods and unique information about metabolic processes within living systems.

Since the public release of the SIVIC software with C-13 HP MR capabilities on July 2011, there have been 5,354 SIVIC binary and source downloads and 1,236 data downloads from the portal. The project e-mail list currently has 40+ subscribers outside of UCSF. We have gotten great feedback from the service project investigators using this software as well as from many other sites using this powerful free software. The feedback from outside users has positively impacted the analysis developments in this TR&D.

We will offer regular training sessions for users associated with the Collaborative and Service Projects, as well as ongoing dialogue about the ease of use and requirements for new capabilities. Contributions from researchers in other institutions are not only welcomed but also encouraged through free, open sharing of the source code and methodology.

Collaborative Projects

Project 1: Investigating Oncogene Expression and Inhibition

PI: Andrei Goga MD, PhD

This molecular biology research is designed to investigate the underlying mechanisms that cause carcinogenesis with oncogene expression and following oncogene inactivation, cause abrupt cell cycle arrest, cell death and tumor regression. This project investigates the role of oncogenes in cancer metabolic changes using a variety of tools including hyperpolarized carbon-13 MR.

Project 2: Noninvasive Assessment of Renal Tumors and Diabetic Nephropathy

PI: Zhen Jane Wang MD

The goal of this work is to a) assess renal tumor metabolic profile using hyperpolarized 13C MR using a multi-probe approach, pyruvate, bicarbonate, urea, and dehydroascorbate (DHA), as a mean to differentiate benign/indolent from aggressive renal tumors, and to assess early treatment response; and b) will develop hyperpolarized 13C MR methods to interrogate key metabolic changes underlie diabetic nephropathy, namely altered oxidative stress (via 13C DHA) and glycolytic metabolism (via 13C fructose).

Project 3: MR Metabolic Imaging of Targeted Therapies & Metabolic Reprogramming in Brain Tumors

PI: Sabrina Ronen PhD

This research aims to better characterize brain tumors and to address the currently unmet need for non-invasive imaging methods to monitor the effect of PI3K/AKT/mTOR inhibitors. This will inform on drug delivery and molecular response, and will enable longitudinal monitoring of drug action at the tumor site. It will provide a tool to help optimize therapeutic regimens that are specifically tailored to the tumor and ultimately could result in more personalized care for GBM patients enhancing quality of life and outcome. In the long term the same approach could be implemented in other types of cancer that are driven by PI3K/AKT/mTOR signaling.

Project 4: Molecular Imaging Probes of ROS/REDOX and Interstitial pH

PI: David Wilson MD, PhD

This project seeks to develop and investigate new ascorbate-based hyperpolarized MRI biomarkers in preclinical animal models. This project also compares this cutting-edge MRI technology to a method already used in the clinic, positron emission tomography (PET) in order to address how these two complementary techniques might best serve the needs of cancer patients.

Project 5: Hyperpolarized C-13 MR Pulse Sequence Developments for Novel Contrast

PI: Peder Larson PhD

This project will develop and test new HP C-13 metabolite diffusion MRI methods to non-invasively measure metabolism and cellular transport. Both of these mechanisms are highly implicated in aggressive types of cancer, as well as other diseases such as kidney failure and non-alcoholic fatty liver disease. This method has significant potential to improve healthcare by better characterizing disease severity and improving outcome predictions following treatment.

Project 6: Molecular Imaging of Prostate Cancer - from realistic pre-clinical models to patients

PIs: Henry VanBrocklin PhD, Rahul Aggarwal MD, Donna Peehl PhD

The long-term goal of this project is to provide companion MR imaging biomarkers that can be used to tailor treatment to individual prostate cancer patients with advanced disease and to benefit future preclinical studies of new therapies and subsequent clinical trials.

Project 7: Molecular Imaging for Detection and Treatment Monitoring of Arthitis

PI: John MacKenzie MD

Monitoring the disease status of autoimmune disorders such as rheumatoid and juvenile idiopathic arthritis requires better quantitative, objective, and noninvasive biomarkers. The overall goal is to develop and study hyperpolarized carbon-13 imaging biomarkers for the detection and treatment monitoring of autoimmune diseases.

Project 8: Molecular HP C-13 MRI of Renal Transport and Metabolism

PIs: Cornelius von Morze PhD, David Pearce MD

Existing clinical markers for early renal disease are very limited. Better monitoring and management of renal disease is a pressing unmet medical need. The overall goal of this collaborative project is to develop the application of new hyperpolarized carbon-13 (13C) MRI technology for monitoring renal disease. The researchers will investigate new contrast mechanisms based on novel hyperpolarized (HP) 13C MR molecular imaging contrast agents to probe key renal transport and metabolic processes in preclinical models.

Project 9: Translating HP 13C MRI for Assessing Drug Target Inhibition in Phase 1 Trials

PI: Pamela Munster MD

The goal of this academic-industrial collaborative research project is to accomplish the clinical translation of the “next-generation imaging technology” hyperpolarized C13 MRI to address the unmet clinical need of quantifying metabolic response to targeted therapy (e.g. mTOR pathway inhibitors) non-invasively in patients with advanced malignancies.

Project 10: Imaging and Tissue Correlates to Optimize Management of Glioblastoma

PI: Susan Chang MD

The purpose of this P01 project is to develop and test novel MR metabolic imaging approaches that will help to distinguish recurrent tumor from normal brain and treatment effects in patients with glioblastoma (GBM). The prognosis for patients with these high grade lesions is relatively poor and identifying more effective treatments is a priority for the neuro-oncology community. Our hypothesis is that integrating multi-parametric MR imaging with novel H-1 MR spectroscopic imaging techniques and new hyperpolarized C-13 metabolic imaging methods will provide a better definition of tumor burden and will help to resolve the ambiguities inherent in conventional imaging.