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

Brian Christopher Ward, Purdue University

Abstract

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 $1.18 billion. While many therapies for abdominal adhesions have been attempted, the need for a definitive therapy to prevent or even reduce abdominal adhesions still exists. 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.

Degree

Ph.D.

Advisors

Panitch, Purdue University.

Subject Area

Biomedical engineering

COinS