• Hypothesis 1: The plasma proteomic signatures of the three main phenotypes of amputation pain are different because the biological mechanisms responsible for each phenotype are also different. Proteins that are quantitatively different in the plasma of amputees with each phenotype represent the products of mechanistic candidate genes for the observed clinical pain state.
• Hypothesis 2: Individual susceptibility to amputation pain phenotype (phantom pain, peripheral neuralgia/neuroma pain or CRPS) is determined in part by genetic variation. Deep re-sequencing in the above candidate genes in amputees with each phenotype will reveal novel variants that predict the phenotype most likely to develop in any given amputee, and further explain the biology of each subtype of chronic pain.

Specific Aims:

• Specific Aim 1:
  • (a) We will describe the early and late proteomic signatures of phantom pain, neuralgia, and CRPS using unbiased plasma proteomics and novel class assignment statistics.
  • (b) We will describe the biological mechanisms responsible for each pain type in terms of the circulating peptides that discriminate them.
• Specific Aim 2:
  • (a) We will use the data from Aim 1 to generate a list of phenotype-specific candidate genes with proven functional relevance for each clinical pain subtype.
  • (b) We will resequence the candidate genes from Aim 2(a) using DNA from amputees of each pain subtype in order to discover novel variants capable of discerning each pain phenotype.

Study Design: We will collect data and specimens from approximately 350 existing and 100 prospective veterans, who will represent discovery and validation populations, respectively. From the discovery population, we will identify mechanistically relevant proteomic and genomic biomarkers capable of discerning the three main subtypes of chronic amputation pain, the validity of which we will confirm in the prospective population.

Impact: In addition to providing military and civilian physicians with new biomarkers of chronic pain states, we will establish a biorepository and matching clinical database of the transition from acute to chronic pain in soldiers returning from theater as they enter the rehabilitation phase of their injury. This will have immeasurable value for scientific projects stretching well beyond the immediate focus of this grant application.

Project/Task Area: Project: Rehabilitation. Task: Acute and Chronic Pain Management.