TTUHSC School of Medicine
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Gail Cornwall, Ph.D.

Associate Professor gail.cornwall@ttuhsc.edu

Biography

Research Interests

Functional role of the cystatin CRES in sperm maturation and fertilization

My laboratory studies the molecular events that govern sperm maturation in the epididymis to ultimately provide new therapies for infertile couples as well as to provide potential targets for the development of male contraceptives. In particular my lab studies the CRES (cystatin-related epididymal spermatogenic) protein that defines a new reproductive-specific subgroup within the cystatin superfamily of cysteine protease inhibitors. In vitro CRES inhibits the serine protease prohormone convertase 2, an enzyme with important roles in the activation of prohormones in the neuroendocrine system. We propose that CRES, while structurally a cystatin, may have evolved to perform unique functions as mediators of substrate-specific serine proteases which may activate critical molecules important for sperm maturation and fertilization. In separate studies we are also studying the role of PC4 (prohormone convertase 4) in sperm function since mice lacking the PC4 gene are infertile possibly due to the lack of appropriate proteolytic activation of important fertilization molecules. We use mouse models including CRES and PC4 gene knockout mice in our studies.

Protein amyloidogenesis in the epididymis: mechanisms and biological significance

The abnormal accumulation of aggregated protein, also known as amyloid, is associated with degenerative diseases including Alzheimer's and Parkinson's disease. Previously disease was thought to result from the mechanical disruption of cell function due to the presence of insoluble protein aggregates. However, accumulating evidence indicates that soluble oligomeric forms of proteins, precursors to amyloid, are cytotoxic and may be the causative form. Because of the active secretion of proteins and profound removal of fluid by the epididymal epithelium, macromolecular crowding is likely to occur in the tubular lumen of the epididymis causing amyloid-type protein aggregation. Since the epididymis plays a critical role in sperm maturation, surveillance/clearance mechanisms must guard against proteins that misfold and form aggregate/amyloid structures in the lumen that could be cytotoxic to spermatozoa. Our studies demonstrate that CRES is an amyloidogenic protein and forms soluble oligomeric and ultimately Congo Red reactive fibrillar structures common to proteins associated with neurodegenerative diseases. Within the normal mouse epididymal lumen CRES also forms soluble and insoluble oligomeric complexes with no obvious associated pathologies since the mice are fertile. We hypothesize that transglutaminase, a calcium-dependent enzyme that forms stable crosslinks in proteins, may divert CRES from the amyloidogenic pathway by crosslinking it into a nontoxic amorphous structure that could ultimately be endocytosed in later epididymal regions. Thus transglutaminase may function as a mechanism of quality control for misfolded proteins in the extracellular space. Studies are currently ongoing to examine the biological significance of the CRES oligomeric structures and mechanisms, including transglutaminase, which may protect against cytotoxicities associated with amyloid structures. These studies will not only contribute to our understanding of processes integral for the maintenance of normal reproductive function but may provide novel insights of extracellular quality control mechanisms in general, possibly leading to new therapies for diseases associated with extracellular aggregated proteins such as Alzheimer's disease.

Recent Publications