Abstract:
Myelin basic
protein (MBP) promotes growth of myelin sheath throughout the nervous system by
binding to the lipids on the myelin membrane (Boggs, 2006). However when a
malignant cell is formed, the abnormal cell inhibits the transmission of
electric signals across synapses (Kaur et al., 2008). MBP has the ability to
distinguish the difference between a normal and malignant Schwann cell due to
deletions within the MBP gene sequence (Kaur et al., 2008).
Figure 1 Myelin Basic Protein: Computer
model of the protein. Human myelin basic protein by binding it to a leukocyte
antigen (Smith et al., 1998).
Aim 1: Select for the protein
A
multi-layered process will be involved in the selection for MBP. Aptamers, used
as RNA protein markers in this case, will be selected for myelin basic protein.
Aptamers bind to proteins with high specificity and affinity to the specific
protein target. This is because aptamers are about one-tenth the size of an
antibody (Boggs, 2006). This provides a set of tools that aid in area of
therapeutic diagnostics in medicine. MBP itself is not a large protein (only
18.5 kDa); thus using an aptamer, which is even smaller, will increase chances
of binding to the protein (Saxe et al., 1985). By selecting for MBP, the gene
sequence of the protein can be verified before further development of an
aptamer to distinguish between a normal and malignant cell. If successful,
further tests can be conducted to see if the aptamer can deliver a drug or
select against a mutate MBP. The first step is to find an aptamer that binds to
this specific protein.
The target can
be ordered from US Biologicals at $327.00 per milligram and $2.40 per round
(400pmol).
References:
Boggs JM (2006) Myelin
basic protein: a multifunctional protein. Cell Mol Life Sci. 63:
1945–1961.
Eylar EH, Brostoff S, Hashim G, Caccam J,
Burnett P (1971). Basic A1 protein of the myelin membrane. The complete amino
acid sequence. J. Biol. Chem. 246 (18): 5770–84.
Gragoudas ES, Adamis AP, Cunningham ET Jr,
Feinsod M, Guyer DR (2004). Pegaptanib for neovascular age-related macular
degeneration. N Engl J Med. 351(27):2805-16.
Kaur
G, Roy
I (2008).
Therapeutic applications of aptamers. National Institute of Pharmaceutical
Education and Research (NIPER). Expert Opin Investing Drugs.
Meinl, Weber, Drexler,
Morelle, Ott, Saruhan-Direskeneli, Goebels, Ertl, Jechart, Giegerich (1993).
Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis.
Complexity of the response and dominance of nested epitopes due to recruitment
of multiple T cell clones. J Clin Invest. 92(6):2633–2643
Saxe DF, Takahashi N, Hood
L, Simon MI (1985). Localization of the human myelin basic protein gene (MBP)
to region 18q22----qter by in situ hybridization. Cytogenet. Cell Genet.
39 (4): 246–9.
Smith, K.J., Pyrdol,
J., Gauthier, L., Wiley, D.C., Wucherpfennig, K (1998). Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with
a peptide from human myelin basic protein.
J.Exp.Med. 188: 1511-1520
Wang C, Neugebauer U,
Bürck J, Myllykoski M, Baumgärtel P, et al. (2011). Charge Isomers of Myelin
Basic Protein: Structure and Interactions with Membranes, Nucleotide Analogues,
and Calmodulin. PLoS ONE 6(5): e19915.
Warren, K.J., Catz, I.,
Steinman, L. (1995). Fine specificity of the antibody response to myelin basic
protein in the central nervous system in multiple sclerosis: The minimal B-cell
epitope and a model of its features. Proc. Natl. Acad. Sci. USA. 92:
11061-11065.
Yin Zhang,
Hao Hong,
Weibo Cai
(2011). Tumor-Targeted Drug Delivery with Aptamers. Current Medical Chemistry 1. 18(27):
4185–4194.
Research Proposal:
https://docs.google.com/document/d/1iiFltUcxxQ39oUpegZl-CNKEM1p1RdXQlP2_njopEnA/edit?usp=sharing
1st Progress Report:
https://docs.google.com/file/d/0By_LVGU6rig_aTc4b2I4aG5GWmc/edit?usp=sharing