OHSU

Thomas R. Shearer, Ph.D.

Thomas R. Shearer Professor and Chair

Research Interests

Studies are focused on providing a detailed mechanism for the role of calcium-activated proteases (calpains) in lens. The overall hypothesis being tested is that proteolysis by calpains is essential for limited truncation, tighter packing of truncated b-crystallins, and rearrangement of the cytoskeletal elements occurring during normal lens fiber differentiation and maturation. During cataract formation, over-activation of calpains by massive influx of calcium produces rapid proteolysis and light scattering because the truncated crystallins are no longer properly ordered. Studies from our labs produced several unexpected findings relevant to this hypothesis: Activity of lens-specific calpain Lp82, a splice variant of muscle p94, and not m-calpain, was most strongly associated with cataract formation in young rodents. Further, calpain 10 was discovered as a third ubiquitous calpain in human lens, and calpain 10 was markedly increased in diabetic cataracts in rats. Lp82, Lp85 ( a low-abundance splice variant in lens), and calpain 10 may truncate specific lens proteins or cleave proteins at unique sites necessary for proper lens maturation or pathologic cataract formation. To test these ideas, three specific aims are being pursued:
  1. Determine the biochemical properties and substrates of Lp82.
  2. Determine if p94 variants assume the role of rodent Lp82 in human lenses and are responsible for unexplained proteolysis in human lenses.
  3. Define the roles of calpain 10 in human lens.

Research Support

National Institutes of Health
Senju Pharmacetical Co., Ltd

Representative Publications

Shih M, Ma H, Nakajima E, David LL, Azuma M, Shearer TR. Biochemical properties of lens-specific calpain Lp85.Exp Eye Res. 2005 Jul 26; [Epub ahead of print]

Tamada Y, Nakajima E, Nakajima T, Shearer TR, Azuma M. Proteolysis of neuronal cytoskeletal proteins by calpain contributes to rat retinal cell death induced by hypoxia. Brain Res. 2005 Jul 19;1050(1-2):148-55.

Nakajima E, Nakajima T, Minagawa Y, Shearer TR, Azuma M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. J Pharm Sci. 2005 Apr;94(4):701-8.

Ma H, Nakajima E, Shih M, Azuma M, Shearer TR. Expression of calpain small subunit 2 in mammalian tissues. Curr Eye Res. 2004 Oct-Nov;29(4-5):337-47.

Azuma M, Sakamoto-Mizutani K, Nakajima T, Kanaami-Daibo S, Tamada Y, Shearer TR. Involvement of calpain isoforms in retinal degeneration in WBN/Kob rats. Comp Med. 2004 Oct;54(5):533-42.