Once considered a metabolically passive organ responsible only for gas exchange, the lung has been shown to perform a variety of critical roles in maintaining body homeostasis in the last few decades. Studies show that some of these homeostatic processes are compromised in lung disease and the lung itself may be damaged by exposure to the products of its regulation and deactivation pathways. While advances in imaging methods have enabled new approaches for structural and functional characterization of pulmonary disorders and their role in gas exchange, imaging methods capable of providing information about the molecular and cellular pathways of these metabolic processes that maintain homeostasis are less understood and developed. This proposal seeks to develop agents specific to three of the more rapid and better-characterized metabolic roles of the lung. Specifically, these include the regulation of glycolytc intermediates, amino acid levels, and vasoactive amines in both the lung tissue and the blood plasma. Significant evidence exists that each metabolic role is modified in obstructive disease, or in conditions that lead to or exacerbate the disease. The work is aided by the development of general techniques to produce and study hyperpolarized 13C probes using high-sensitivity NMR and imaging, and recent results which show how the hyperpolarized state may be maintained for a longer period than was previously thought possible. Furthermore, the targets chosen here are well suited to hyperpolarized 13C technology because they are among the most rapid molecular events that take place within the organ. The central hypotheses of this proposal are that 1) hyperpolarized probes, beyond those in use for studying ventilation and gas exchange, will provide a sensitive probe of the ability of the lung to achieve homeostasis, 2) derived metrics are detectably dependent on disease state relevant to human obstructive disease, and 3) these probes are extensible to imaging applications. In addressing these hypotheses we propose the following specific aims: 1) Development and testing of molecular probes for studying glycolysis, amino acid synthesis, metabolism of inflammatory cells, and non-metabolitzed agents for tissue perfusion measurement, 2) Testing the applicability of each of the aforementioned probes in the isolated, perfused rat lung, 3) Studying the primary importance of redox states in healthy diseased lung, and 4) Performing a series of metabolic studies in rat and pig models of lung disease. Many pulmonary disorders and in particular COPD are characterized by dysfunctional whole-body energy metabolism, which may in part result from the lung's failure to maintain homeostasis of glycolytic intermediates. We believe that the development of hyperpolarized agents targeted to lung molecular activity and accomplishment of the above specific aims will address the shortcomings of existing techniques for studying lung homeostatic functions and their associations with disease state.

Public Health Relevance

The goal of this project is to develop noninvasive metabolic probes for assessment of lung disease and to develop lung redox imaging using hyperpolarized 13C technology. Completion of the specific aims will provide insights about disease pathogenesis and facilitate new agents for obstructive disease diagnosis and staging.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL116342-01
Application #
8417368
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Program Officer
Lin, Sara
Project Start
2012-09-25
Project End
2015-06-30
Budget Start
2012-09-25
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$400,000
Indirect Cost
$150,000
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Siddiqui, Sarmad; Kadlecek, Stephen; Pourfathi, Mehrdad et al. (2016) The use of hyperpolarized carbon-13 magnetic resonance for molecular imaging. Adv Drug Deliv Rev :
Drachman, Nicholas; Kadlecek, Stephen; Pourfathi, Mehrdad et al. (2016) In vivo pH mapping of injured lungs using hyperpolarized [1-(13) C]pyruvate. Magn Reson Med :
Cereda, Maurizio; Xin, Yi; Meeder, Natalie et al. (2016) Visualizing the Propagation of Acute Lung Injury. Anesthesiology 124:121-31
Cereda, Maurizio; Xin, Yi; Hamedani, Hooman et al. (2016) Mild loss of lung aeration augments stretch in healthy lung regions. J Appl Physiol (1985) 120:444-54
Shaghaghi, Hoora; Kadlecek, Stephen; Siddiqui, Sarmad et al. (2015) Ascorbic acid prolongs the viability and stability of isolated perfused lungs: A mechanistic study using 31P and hyperpolarized 13C nuclear magnetic resonance. Free Radic Biol Med 89:62-71
Kadlecek, Stephen; Shaghaghi, Hoora; Siddiqui, Sarmad et al. (2014) The effect of exogenous substrate concentrations on true and apparent metabolism of hyperpolarized pyruvate in the isolated perfused lung. NMR Biomed 27:1557-70