Enabling widespread use of high resolution imaging of oxygen in the brain As. essment of brain oxygenation on the microscopic level has the potential to transform our understanding of important clinical problems, such as stroke, Alzheimer's disease, dementia, chronic hypertension, and brain cancer, facilitating the development of new therapies and helping to improve clinical imaging and treatment protocols. Until now, no technology has been capable of microscopic oxygen imaging in the brain with high spatial and temporal resolution. Over the past several years we have developed a method, termed two-photon phosphorescence lifetime microscopy of oxygen (2PLM), which has the unique capability of fulfilling this niche. This is the only imaging method that allows high resolution mapping of brain oxygenation in real time. We propose to establish a sustainable resource for the dissemination of 2PLM of oxygen, making it available to interested researchers across different fields of neurology and neuroscience. 2PLM is a combination of state-of-the-art two-photon enhanced phosphorescent probes and a unique variant of two- photon laser scanning microscopy. In this project we will optimize and scale up synthesis of the oxygen probes, making them available for interested users. We will incorporate recently developed, dedicated commercial electronic components into 2PLM setups. We will also optimize algorithms and produce user- friendly software for those interested in setting up their own 2PLM systems. In addition, we will organize a resource center where users will be able to receive training and run pilot experiments. The work will be performed at two closely collaborating sites: the University of Pennsylvania (probe chemistry) and MGH (imaging setup). Our laboratories have a long history of productive collaboration. We also collaborate broadly with many researchers across the field interested in oxygen imaging. This will allow us to establish an effective infrastructure for the resource center, making the 2PLM of oxygen technology accessible to a broad user base.

Public Health Relevance

In this project we propose to establish a high-impact Resource center for dissemination of two-photon phosphorescence lifetime microscopy of oxygen (2PLM) - the unique technology that enables high resolution mapping of brain oxygenation in real time. We will optimize and scale up synthesis of two-photon phosphorescent oxygen probes, incorporate recently developed commercial electronic components into 2PLM setups, optimize 2PLM algorithms, produce user-friendly software for expert and non-expert users and establish a center for training new 2PLM users. The work will be performed in two sites responsible for the development of 2PLM and linked by strong collaborative ties: University of Pennsylvania (probe chemistry) and MGH (imaging setup).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Resource-Related Research Projects (R24)
Project #
5R24NS092986-03
Application #
9284535
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Koenig, James I
Project Start
2015-07-15
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Friedman, Elliot S; Bittinger, Kyle; Esipova, Tatiana V et al. (2018) Microbes vs. chemistry in the origin of the anaerobic gut lumen. Proc Natl Acad Sci U S A 115:4170-4175
Xu, Kui; Boas, David A; Sakadži?, Sava et al. (2017) Brain Tissue PO2 Measurement During Normoxia and Hypoxia Using Two-Photon Phosphorescence Lifetime Microscopy. Adv Exp Med Biol 977:149-153
Ravotto, Luca; Chen, Qi; Ma, Yuguo et al. (2017) Bright long-lived luminescence of silicon nanocrystals sensitized by two-photon absorbing antenna. Chem 2:550-560
Kisler, Kassandra; Nelson, Amy R; Rege, Sanket V et al. (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20:406-416
Zhang, Cong; Moeini, Mohammad; Lesage, Frédéric (2017) Spatial landscape of oxygen in and around microvasculature during epileptic events. Neurophotonics 4:010501
Sakadži?, Sava; Yaseen, Mohammad A; Jaswal, Rajeshwer et al. (2016) Two-photon microscopy measurement of cerebral metabolic rate of oxygen using periarteriolar oxygen concentration gradients. Neurophotonics 3:045005
Gagnon, Louis; Smith, Amy F; Boas, David A et al. (2016) Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation. Front Comput Neurosci 10:82
Yaseen, Mohammad A; Srinivasan, Vivek J; Gorczynska, Iwona et al. (2015) Multimodal optical imaging system for in vivo investigation of cerebral oxygen delivery and energy metabolism. Biomed Opt Express 6:4994-5007