The long-range goal is to identify the genetic programs controlling the formations of specific sensory pathways and to gain insight into the molecular and cellular basis of pain perception. In this renewal application, we try to address two major knowledge gaps. First, most clinically relevant pain is derived from deep tissues, such as muscle, joint, bone, and visceral organs. Despite this clinical significance, the molecular and cellular basis of "deep" pain is still poorly understood, which is in stark contrast to the tremendous progress made in the past decades in understanding cutaneous pain.
In Aim 1 studies, we will establish a molecular map for sensory neurons innervating distinct deep tissues. We will also determine if Meis1 represents the first transcription factor that controls the development of deep tissue sensory neurons. Second, the cellular basis of mechanical allodynia (pain evoked by innocuous mechanical stimuli), a hallmark for most, if not all, chronic pain disorders, needs further clarification. In case of neuropathic pain, it was proposed that central disinhibition will allow low threshold myelinated A? mechanoreceptors to directly activate the pain pathways. However, a recent study proposed that unmyelinated low threshold c- mechanoreceptors, marked by the expression of the vesticular glutamate transporter VGLUT3, may play an essential role in the readout of the mechanical allodynia. Our preliminary genetic fate-mapping studies show that VGLUT3 lineage neurons are in fact composed of both 1) unmyelinated c-mechanoreceptors that form free nerve endings in the skin epidermis and lanceolate endings around hair follicles, and 2) myelinated m-mechanoreceptors that form the Merkel-cell neurite complex.
In Aim 2, we will determine if Zfp521, a transcription factor expressed exclusively in VGLUT3 lineage c-mechanoreceptor, is necessary for the development of these c-mechnaoreceptors. We will also determine if mechanical allodynia is differentially affected in mice that will have a selective developmental defect in VGLUT3 lineage c- mechanoreceptors or a defect in the VGLUT3-expressing Merkel cell-neurite complex. Together, these studies will gain insight into 1) the genetic programs that control the formation of the deep tissue pain pathways, and 2) the identities of low threshold mechanoreceptors mediating the readout of mechanical allodynia.

Public Health Relevance

Most clinically relevant chronic pain disorders are originated from deep tissues, such as muscle, bone, joints, and visceral organs. In the fullness of time, the work may allow us to identify the first transcription factor that selectively controls the assembly of these deep tissue pain pathways. The compiling of a molecular map of neurons innervating variant deep tissues will also offer new potential targets for treating different deep tissue pain. Finally, the understanding of the cellular basis of mechanical allodynia may provide new thinking or strategies to treat chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018025-08
Application #
8685760
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2006-12-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
$415,000
Indirect Cost
$165,000
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Ma, Qiufu (2014) Merkel cells are a touchy subject. Cell 157:531-3
Prescott, Steven A; Ma, Qiufu; De Koninck, Yves (2014) Normal and abnormal coding of somatosensory stimuli causing pain. Nat Neurosci 17:183-91
Lou, Shan; Duan, Bo; Vong, Linh et al. (2013) Runx1 controls terminal morphology and mechanosensitivity of VGLUT3-expressing C-mechanoreceptors. J Neurosci 33:870-82
Yang, Fu-Chia; Tan, Taralyn; Huang, Tianwen et al. (2013) Genetic control of the segregation of pain-related sensory neurons innervating the cutaneous versus deep tissues. Cell Rep 5:1353-64
Ma, Qiufu (2012) Population coding of somatic sensations. Neurosci Bull 28:91-9
Liu, Yang; Ma, Qiufu (2011) Generation of somatic sensory neuron diversity and implications on sensory coding. Curr Opin Neurobiol 21:52-60
Ma, Qiufu (2010) Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest 120:3773-8
Abdel Samad, Omar; Liu, Yang; Yang, Fu-Chia et al. (2010) Characterization of two Runx1-dependent nociceptor differentiation programs necessary for inflammatory versus neuropathic pain. Mol Pain 6:45
Liu, Yang; Abdel Samad, Omar; Zhang, Ling et al. (2010) VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68:543-56
Stifani, Stefano; Ma, Qiufu (2009) 'Runxs and regulations'of sensory and motor neuron subtype differentiation: implications for hematopoietic development. Blood Cells Mol Dis 43:20-6

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