The goal of this Bioengineering Research Partnership is to develop new techniques for the comprehensive assessment of lung function by producing hyperpolarized tracer molecules (bicarbonate/CO2, betaine, cyclopropanedimethanol, and pyruvate) for MR imaging and spectroscopy of both normal and diseased lungs. We will use the method of dynamic nuclear polarization (DNP) to produce hyperpolarized 13C-labeled compounds proposed in this application. First, we will improve the signal-to-noise for hyperpolarized tracer imaging by building a polarizer that operates in a 5.0 T magnetic field. Second, we will determine the characteristics of 13C-bicarbonate, betaine, cyclopropanedimethanol, and [1-13C]pyruvate under conditions relevant to molecule freezing, hyperpolarization, dissolution, and transport. The management and understanding of these technical parameters is a prerequisite to successful in vivo studies and to obtaining high levels of polarization of the proposed molecules. Although the physical descriptions of the DNP process do not include significant influence from the chemical environment of the sample, the achievable polarization level represents a balance between spin-diffusion, polarization transfer, and relaxation. To this end, we will determine the optimal polarization conditions, including the specific formulation of each molecule and its concentration, the concentration of the radical, polarization enhancer (gadolinium complex), co-freezing agents and the optimal microwave frequency for DNP, all compared against polarization build-up time, T1 relaxation time and the plateau polarization level. Third, we will establish in vitro models of these hyperpolarized substrates and will characterize their NMR and biochemical properties in physiologically relevant environments. To determine the effectiveness of these molecules as hyperpolarized agents for the proposed study, it is not sufficient to show that the molecule can be highly polarized in a reasonable time-scale in the DNP apparatus. It is equally important to characterize the properties of the tracers as they travel through the circulatory system towards the lungs. Forth, we will develop a technique for pH mapping of the lung through measurement of the 13C-bicarbonate/13CO2 balance after intravenous administration of 13C-bicarbonate, as well as assessing exchange of 13CO2 from the pulmonary vasculature to the alveolar space through measurement of the CO2/bicarbonate apparent T1. pH is a key parameter in most pathologies and mapping of this quantity has already been demonstrated through localized measurement of the pH-dependent bicarbonate/CO2 balance. Finally we will study pH, gas exchange and metabolism in an animal model of COPD with hyperpolarized 13C-bicarbonate and 13C-pyruvate. Assessment of lung function and pathology remains a clinical problem. We will test the application of methods developed above to a model of lung disease (COPD), and refine qualitative measures of metabolism and perfusion developed earlier. We will seek patterns characteristic to the diseased subject and, where possible, compare them to established methods of measuring pH, perfusion, gas exchange and metabolism. Keywords: Dynamic Nuclear Polarization, Hyperpolarized Carbon-13 MR Imaging, Lung Metabolism, pH Measurements, Gas Exchange.

Public Health Relevance

Hyperpolarized carbon-13 MR imaging and spectroscopy has the potential to reveal metabolic and physiological alterations in lung induced by chronic obstructive pulmonary diseases with an unprecedented sensitivity. Important clinical applications include early diagnosis of emphysema and cystic fibrosis and to expand the knowledge base in this area for discovering new therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB010208-05
Application #
8675742
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (50))
Program Officer
Liu, Guoying
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$1,052,638
Indirect Cost
$394,739
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shaghaghi, Hoora; Kadlecek, Stephen; Deshpande, Charuhas et al. (2014) Metabolic spectroscopy of inflammation in a bleomycin-induced lung injury model using hyperpolarized 1-(13) C pyruvate. NMR Biomed 27:939-47
Kuzma, N N; Hakansson, P; Pourfathi, M et al. (2013) Lineshape-based polarimetry of dynamically-polarized (15)N2O in solid-state mixtures. J Magn Reson 234:90-4
Pourfathi, M; Kuzma, N N; Kara, H et al. (2013) Propagation of dynamic nuclear polarization across the xenon cluster boundaries: elucidation of the spin-diffusion bottleneck. J Magn Reson 235:71-6
Pullinger, B; Profka, H; Ardenkjaer-Larsen, J H et al. (2012) Metabolism of hyperpolarized [1-(13) C]pyruvate in the isolated perfused rat lung - an ischemia study. NMR Biomed :