The overall goal of this project is to determine the contribution of sensory neuron mitochondrial dysfunction and TRP channel sensitization to pain in sickle cell disease (SCD), including the development of chronic pain. SCD is accompanied by crippling pain during acute sickling episodes that increases in severity and frequency with age. By adulthood, approximately 50% of SCD patients also suffer from chronic pain. SCD involves repeated ischemia-reperfusion injury and increased neutrophil numbers/activity, which results in elevated reactive oxygen species (ROS) generation and oxidative stress. This can lead to mitochondrial dysfunction and sensitization of Transient Receptor Potential (TRP) ion channels. We show that mice with severe SCD exhibit evidence for ongoing pain and pronounced pain-like behavior in response to cold, mechanical and heat stimuli. Our preliminary data also indicate that sensory neurons from sickle mice have severely dysfunctional mitochondria. We hypothesize that ROS and oxidative stress induce mitochondrial dysfunction and TRP channel sensitization in sickle sensory neurons, leading to the chronic pain and thermal hypersensitivity that is characteristic of this devastating disease.
Aim 1 will determine the time course of neuronal mitochondrial dysfunction and pain sensitivity in sickle mice from age 2 to 12 weeks.
Aim 2 will determine whether sensitized TRPA1 or TRPM8 channels underlie the cold hypersensitivity and primary afferent sensitization in sickle mice.
Aim 3 will determine whether treatment with mitochondrial-targeted antioxidants reverses the pain behavior and primary afferent sensitization in sickle mice. These interrelated Aims provide a multifaceted approach that will define the mechanisms by which mitochondrial dysfunction and TRP channel sensitization lead to the devastating pain observed in SCD. Furthermore, this study targets specific cold-sensitive ion channels (TRPA1 and TRPM8) on sensory neurons because cold pain and cold hypersensitivity are a major complaint of patients with SCD. Data from this study will improve our understanding of the complex SCD pain syndromes and should aid in identifying novel therapeutic targets

Public Health Relevance

Sickle cell disease is an inherited disorder of the red blood cell causing a shape change and clogging blood vessels, resulting in severe pain and suffering. The pain and disability are even more severe in adults than in children. In this grant, we intend to study the precise nerve cells and pathways that sense and influence the pain so that we can develop new methods to treat sickle cell disease more safely and effectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070711-08
Application #
9267546
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03)M)
Program Officer
Oshinsky, Michael L
Project Start
2009-09-30
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
8
Fiscal Year
2017
Total Cost
$343,930
Indirect Cost
$104,193
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Moehring, Francie; Halder, Priyabrata; Seal, Rebecca P et al. (2018) Uncovering the Cells and Circuits of Touch in Normal and Pathological Settings. Neuron 100:349-360
Cowie, Ashley M; Moehring, Francie; O'Hara, Crystal et al. (2018) Optogenetic Inhibition of CGRP? Sensory Neurons Reveals Their Distinct Roles in Neuropathic and Incisional Pain. J Neurosci 38:5807-5825
Sadler, Katelyn E; Zappia, Katherine J; O?Hara, Crystal L et al. (2018) Chemokine (c-c motif) receptor 2 mediates mechanical and cold hypersensitivity in sickle cell disease mice. Pain 159:1652-1663
Moehring, Francie; Cowie, Ashley M; Menzel, Anthony D et al. (2018) Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. Elife 7:
Sadler, Katelyn E; Stucky, Cheryl L (2018) Neuronal transient receptor potential (TRP) channels and noxious sensory detection in sickle cell disease. Neurosci Lett 694:184-191
Moehring, Francie; Waas, Matthew; Keppel, Theodore R et al. (2018) Quantitative Top-Down Mass Spectrometry Identifies Proteoforms Differentially Released during Mechanical Stimulation of Mouse Skin. J Proteome Res 17:2635-2648
Miller, James J; Aoki, Kazuhiro; Moehring, Francie et al. (2018) Neuropathic pain in a Fabry disease rat model. JCI Insight 3:
Brandow, Amanda M; Hansen, Karla; Nugent, Melodee et al. (2018) Children and adolescents with sickle cell disease have worse cold and mechanical hypersensitivity during acute painful events. Pain :
Zappia, Katherine J; O'Hara, Crystal L; Moehring, Francie et al. (2017) Sensory Neuron-Specific Deletion of TRPA1 Results in Mechanical Cutaneous Sensory Deficits. eNeuro 4:
Xiang, Hongfei; Liu, Zhen; Wang, Fei et al. (2017) Primary sensory neuron-specific interference of TRPV1 signaling by AAV-encoded TRPV1 peptide aptamer attenuates neuropathic pain. Mol Pain 13:1744806917717040

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