STUDIES

Functional and Structural Imaging

Hyperpolarization provides a platform for imaging lung physiology with spatial and temporal resolution unattainable with conventional MRI techniques, thus offering the potential for the earlier diagnosis of disease states and the precise monitoring of a patient's response to medical treatment. In FMIG, our goal is to develop gas (3He, 129Xe) MRI techniques for the quantitative assessment of pulmonary structure and physiology parameters such as ventilation blood/air gas exchange, regional partial pressure of oxygen, inflammation and perfusion. These methods of measurement are employed in large and small animals as well as clinical studies of common pulmonary disease models; most notably COPD, emphysema, asthma and cystic fibrosis. This core research theme is executed with an eye towards the identification of changes in pulmonary structure and function associated with disease, a more complete understanding of pathogenesis, and the establishment of a more sensitive testing environment to develop treatments for lung disease.

Metabolic Imaging
Kinetic Metabolism

The advent of novel methods for obtaining and retaining hyperpolarized nuclear spins in solution has allowed for rapid, non-invasive NMR imaging and spectroscopy of isotopes with low natural-abundance and/or intrinsically small magnetic moments. Current interest is focused on developing 13C-labeled hyperpolarized agents as a spectroscopic probe of real-time metabolic activity in vivo and as an imaging agent for monitoring the poorly understood changes in the lung in diesease or conditions of oxidative stress.We also perfrom experimental studies of altered metabolism in heart, liver and braind, and of the greatly accelertarted metabolic processes in cancer.focus is on the poorly understood metabolic changes in the lung in disease or conditions of oxidative stress, but we also perform experimental studies of altered metabolism in heart, liver and brain.

Real-Time Metabolic Profiling

Altered metabolic activity is a hallmark of a variety of life-threatening diseases, including specific types of cancer. Recently, it has been shown that the metabolism of hyperpolarized [1-13C] pyruvate can be monitored in real-time both in vivo and in vitro and, more importantly, that healthy and cancerous tissues/cells may be distinguished based on the quantitative distribution of the metabolites of pyruvate. While it is without a doubt that the role of pyruvate in energy production is significant, the metabolic activity of a wide multitude of important substrates has yet to be fully explored. Our group seeks to develop methods for efficiently and reproducibly hyperpolarizing metabolically relevant substrates with the long-term goal of applying these substrates in studies investigating and quantifying altered metabolism in several clinically-relevant pathologies.

Ventilation and Perfusion Imaging

The primary physiological function of the lung is to supply an adequate amount of oxygen necessary for fulfilling metabolic demands and to remove the carbon dioxide that is formed as a by-product of metabolism. The lung functions most efficiently when ventilation, the process of delivering air to the lungs, is matched with perfusion, the delivery of blood to the lungs. Several pathologies disrupt this matching, which makes real-time assessment of these processes of significant clinical importance. Our group is currently investigating regional perfusion using hyperpolarized 13C MRI to compliment our well-characterized methods for determining regional ventilation using hyperpolarized helium-3 gas.

Hyperpolarization Technology
Optical Pumping

Optical pumping refers to a process by which the random state of an optically active electron is organized through interaction with light. The light is typically circularly polarized, meaning that each photon carries angular momentum, and the aim is to polarize, or align, the electron. This alignment can then be transferred to nuclei of the same or nearby atoms through processes known as spin-exchange [1] and metastability-exchange [2], and the resulting nuclear alignment results in a greatly increased signal in magnetic resonance imaging. Experimental convenience and safety in human studies have led most researchers to focus on MRI using the 'hyperpolarized' gases 3He and 129Xe. Our research focuses on methods to increase the production rate and degree of alignment for these gases while minimizing equipment cost, size, and site upfit requirements in support of more widespread adoption of hyperpolarized gas imaging as a clinical tool in lung disease management. Several recent advances in the field have made this a practical goal, including the use of frequency-narrowed diode lasers as a light source [3] and the advent of 'hybrid' spin-exchange optical pumping [4]. Ongoing projects include research into the complex interaction between hyperpolarized gases and surface magnetism in their container.

Dynamic Nuclear Polarization

A third hyperpolarization method is known as 'Dynamic Nuclear Polarization', in which the large thermal polarization of an unpaired electron in high magnetic field and at low temperature is transferred to a nearby nucleus (usually 13C as well) through an Overhauser-type mechanism. DNP is likely the most general method for hyperpolarization, and our efforts are geared toward measurements of metabolism in a variety of compounds and cell lines, particularly those with applications in understanding the idiosyncrasies of cancer metabolism. Recent results suggest the importance of extending apparatus to operate at higher fields [6] and our applications require larger samples, both of which are the goals of our efforts to redesign the DNP system.

Hyperpolarized Singlet State Studies

The development of hyperpolarized tracers has been limited by short nuclear polarization lifetimes. The dominant relaxation mechanism for many hyperpolarized agents in solution arises from intramolecular nuclear dipole-dipole coupling modulated by molecular motion. It has been previously demonstrated that nuclear spin relaxation due to this mechanism can be removed by storing the nuclear polarization in long-lived, singlet-like states. Ultimately the goal of singlet state research is to extend the longitudinal polarization lifetime of biosensors after dynamic nuclear polarization. This research is currently progressing to both simulating and experimentally measuring the relaxation properties of potential hyperpolarized singlet state 13C biosensor molecules.

Recycling

Because the nuclei most suitable for hyperpolarization (3He, 129Xe, 13C, 15N) are rare and require isolation and purification, methods to recapture them after use are helpful in reducing the cost as these methods become clinically applicable. 3He in particular is essentially absent on earth, and existing supplies come from the decay of tritium in nuclear weapon triggers. Since it is also the easiest compound to re-purify, we are developing systems to extract the gas efficiently from exhaled gas through membrane and cryogenic separation, testing that the gas is suitable for re-hyperpolarization and human rebreathing. These efforts are likely necessary for 3He imaging to be clinically viable.

Rapid Imaging Pulse Sequence Development

Because of the loss of signal due to rapid longitudinal relaxation inherent to hyperpolarized MRI, It is as crucially as important to implement more efficient data aquisition methods and develop rapid imaging pulse sequences acquire as much data as possible to reconstruct images with better spatial and temporal resolutions. At FMIG we develop, simulate and test rapid pulse sequences suited to the applications of mtabolic imaging upon injection of 13C-labled metabolites.

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