Date of Award

1-1-2008

Embargo Period

1-1-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Rick Schnellmann

Second Advisor

Craig Beeson

Third Advisor

Lisa Cunningham

Fourth Advisor

Barbel Rohrer

Fifth Advisor

Douglas Sweet

Sixth Advisor

Gary Wright

Abstract

Calpains are a family of Ca^2+-activated, non-lysosomal, cysteine proteases that have been implicated in a variety of physiological and pathological processes. Currently, the family consists of 14 members, of which eight are typical (calpains 1, 2, 3, 8, 9, 11, 12, and 14) and six are atypical (calpains 5, 6, 7, 10, 13, 15), based on the presence or absence of the Ca^2+-binding domain (domain IV), respectively. The atypical calpain have recently gained attention due to studies that have linked human diseases to mutations in specific calpain genes (Type 2 diabetes linked to calpain 10 and Limb Girdle Muscular Dystrophy linked to calpain 3). Additionally we have previously shown that calpain 10 is localized to the mitochondria of rabbit renal mitochondria and is involved in Ca^2+-induced mitochondrial dysfunction. Beyond this, very little is known about the subcellular localization of calpain 10, especially in species other than the rabbit. In this report we have determined that calpain 10 is present, in an active form, in the mitochondria of three separate species. Additionally, we identified at least 3 separate calpain 10 splice variants in the mitochondria. To further characterize calpain 10 physiology, we developed a model in which we could evaluate the effectiveness of novel calpain 10 specific inhibitor (CYGAK-dimer). CYGAK-dimer inhibits, in a concentration-dependent manner, a maximum of approximately 20% of total cellular cleavage of SLLVY-AMC. This discovery has provided insight into previously unknown characteristics of calpain 10 physiology, indicating that calpain 10 activity is responsible for approximately 20% of total ongoing calpain activity within a cell. In summary, we have explored multiple avenues of calpain 10 biology, providing groundwork for further investigation in the dynamic field of calpain research.

Rights

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