Development of a novel cell-permeant peptide-based inhibitor of MAPKAP-K2 and application of this therapeutic to abdominal adhesion prevention .

摘要

An adhesion occurs when two tissues that normally freely move past each other attach via a fibrous bridge. Abdominal adhesions place a tremendous clinical and financial burden on public health. Adhesions develop after nearly every abdominal surgery commonly causing female infertility, chronic pelvic pain, and, most frequently, small bowel obstruction. A National Hospital Discharge Survey of hospitalizations between 1998 and 2002 reported that 18.1% of hospitalizations were related to abdominal adhesions annually accounting for 948,000 days of inpatient care at an estimated cost of ;Our proposed therapy represents a rational and novel approach for preventing surgical adhesions. By inhibiting mitogen activated protein kinase activated kinase, MAPKAP-K2 (MK2), a kinase associated with actin stress fiber formation and cytokine upregulation that ultimately leads to fibrosis and inflammation, our synthetic, cell-permeant, inhibitor peptide offers the potential of being a rapid, targeted therapy to prevent adhesions. This thesis will present progress made on the three aims of this project: (1) Develop a cell-permeant, peptide-based inhibitor of MK2 with high potency and specificity. (2) Examine the effect of the MK2 inhibitor peptide on human cells relevant to adhesions: mesothelial cells, macrophages, and fibroblasts. (3) Develop and execute in vivo models of abdominal adhesions to determine the efficacy of the MK2 inhibitor peptide in preventing abdominal adhesions.