Primary Department Affiliation: Pulmonary, Allergy, and Critical Care Medicine
Primary Research Area: Respiratory Immunology and Pulmonary Disease
Dr. J. Edwin Blalock, Professor, received his B.S. and Ph.D. degrees from the University of Florida. After Postdoctoral Training at the University of Texas Medical Branch in Galveston, and after spending several years on the faculty there, Dr. Blalock came to UAB in 1986.
The overall objective of our current research is to delineate certain genetic rules that govern the shape and function of proteins and peptides. Specifically, nucleic acids encode amino acid sequences in a binary fashion with regard to hydropathy. We and others have provided compelling evidence that the exact pattern of polar and nonpolar amino acids, rather than the precise identity of particular R groups, is an important driving for protein shape. These design principles are being used:
- to make synthetic peptides specifically targeted to act as agonists and antagonists of Ca++ channels involved in apoptosis and respiratory burst in polymorphonuclear leukocytes (PMN) and
- to make synthetic peptide vaccines as immunotherapeutic agents against autoimmune diseases of the nervous system such as myasthenia gravis (MG) and multiple sclerosis (MS).
- to make antagonists of the PMN chemoattractant peptide, Pro-Gly-Pro (PGP) described below.
We are studying the tripeptide neutrophil chemoattractant N-acetyl PGP, derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and in vivo and in vitro blockade of PGP with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic inflammatory diseases.
In addition, together with Dr. Frans Nijkamp and colleagues at the University of Utrecht, we are evaluating the aforementioned peptide regulators of Ca++ channels for utility in models of asthma. We are also studying the role of PGP in emphysema with colleagues at the University of Utrecht and have begun studies to determine whether PGP is a marker for human chronic lung diseases.
Araga, S., L. Xu, K. Nakashima, M. Villain, and J.E. Blalock. 2000. A peptide vaccine that prevents experimental autoimmune myasthenia gravis by specifically blocking T cell help. FASEB J. 14:185-196.
Villain, M., P.L. Jackson, M.K. Manion, Z. Su, G. Fassina, T.M. Johnson, T.T. Sakai, N.R. Krishna, and J.E. Blalock. 2000. De novo design of peptides targeted to the EF hands of calmodulin. J. Biol. Chem. 274:2676-2685.
Manion, M.K., Z. Su, M. Villain, and J.E. Blalock. 2000. A new type of Ca2+ channel blocker that targets Ca2+ sensors and prevents Ca2+-mediated apoptosis. FASEB J. 14:1297-1306.
Pfister, R.R., J.L. Haddox, J.E. Blalock, C.I. Sommers, L. Coplan, and M. Villain. 2000. Synthetic complementary peptides inhibit a neutrophil chemoattractant found in the alkali-injured cornea. Cornea 19:384-389.
Ten Broeke, R., G. Folkerts, T. Leusink-Muis, H.J. van der Linde, M. Villain, M.K. Manion, F. DeClerck, J.E. Blalock, and F.P. Nijkamp. 2001. Calcium sensors as new therapeutic targets for airway hyperresponsiveness and asthma. FASEB J. 15:1831-1833.
Blalock, JE. 2002. Harnessing a neural-immune circuit to control inflammation and shock. J. Exp. Med. 195:F25-F28.
Weathington, N.M. and J.E. Blalock. 2003. Rational design of peptide vaccines for autoimmune disease: Harnessing molecular recognition to fix a broken network. Expert Review of Vaccines 2:61-73.
Blalock, J.E. 2005. The immune system as the sixth sense. J. Intern. Med. 257:126-138.
Weathington,N.M., A.H. van Houwelingen, B.D. Noerager, P.L. Jackson, A.D. Kraneveld, F.S. Galin, G. Folkerts, F.P. Nijkamp, and J.E. Blalock. 2006. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nature Medicine doi:10.1038/nm1361