The long-range goal of this competitive renewal of a previous R01 is to investigate genetic programs that control pain relay sensory neuron phenotypes in the dorsal spinal cord. During the previous funding interval, my colleagues and I have compiled a genome-scale expression map of transcription factors in the mouse nervous system. Subsequent genetic studies demonstrate that Tlx3, a homeobox class transcription factor, is a pivotal regulator of spinal relay sensory neurons, including specification of both glutamate and peptide neurotransmitters. Furthermore, persistent Tlx3 expression in adult animals is confined to superficial laminae, where putative pain relay neurons are located. The research described here builds upon this preliminary work. The goal of our research over the next five years is to illustrate the roles of Tlx3 in regulating spinal relay nociceptor phenotypes and pain behaviors and to gain insights into the molecular and cellular basis underlying pain perception. We have four specific Aims.
Aim 1 is to determine the roles of Tlx3 in controlling the development of ascending projection neurons that are critical for pain perception.
Aim 2 is to determine how dynamic Tlx3 expression controls lamina organization of the dorsal spinal cord.
Aim 3 is determine the roles of Tlx3 in maintaining dorsal horn excitatory neuron phenotypes, thereby determining if Tlx3-mediated core transcription program is a potential target for pain treatment.
Aim 4 is to determine the roles of Tlx3-dependent differentiation programs in controlling pain behaviors. Each of these aims is built upon a set of preliminary data that lead to a testable hypothesis. A panel of genetic tools that we have already developed will test the predictions of these hypotheses.

Public Health Relevance

Pain management remains a major medical problem in a variety of human diseases. Chronic pain, moreover, is associated with worse disease outcome and depression. In the fullness of time, the work may allow us to determine whether the Tlx3-mediated core transcriptional program is a valid and novel therapeutic target for pain management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047710-10
Application #
8416390
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2004-01-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$342,786
Indirect Cost
$135,914
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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