Chandra Mohan, M.D., Ph.D.

Chandra Mohan, M.D., Ph.D.
Title: “Genetic Simplification of Lupus - A Complex Autoimmune Disease”
Systemic lupus erythematosis is a complex, multi-system autoimmune disease that affects over 1.5 million Americans.  The disease is polygenic in origin and can be studied using inbred strains of lupus-prone and resistant mice. Four genetic loci that affect Lupus susceptibility in the NZM2410 mouse strain (which develops lupus spontaneously) have been identified: Sle1 on chromosome 1; Sle2 on chromosome 4; Sle3 on chromosome 7; and the H2 locus on chromosome 17. By breeding these congenic intervals containing these loci onto the lupus-free B6 genetic background, we have been able to show that each congenic interval impacts the immune system in differently. Hence, a complex autoimmune disease can be dissected out into a series of simpler “monogenic” models. Importantly, intercrossing of these different monocongenic strains reconstitutes full-blown lupus. Dr. Mohan and his colleagues are using these novel strains to understand how these different genetic elements function to breach immune tolerance and induce the renal disease that often afflicts lupus patients. The long-term goal of this research is to identify the culprit genes within these disease intervals and to map out the molecular pathways through which they function.  These types of analyses should lead to more effective therapeutic intervention strategies.

Chandra Mohan is an alumnus of the Sackler School Immunology Graduate Program and presently Associate Professor of Internal Medicine and University of Texas Southwestern Medical School. His research focuses on the genetics of autoimmune disease

	Kelly E. Beazley

Kelly E. Beazley, Cell, Molecular, and Developmental Biology
Exposure to ultraviolet (UV) light is one of the leading causes of tissue damage. In exposed skin, UV light alters DNA and produces genetic changes that contribute to the development of skin cancer. Paradoxically, it has long been known that the cornea, a tissue continually exposed to UV light, is resistant to UV damage. Until recently, the mechanism responsible for the protected status of the cornea was completely unknown. Using a genetic screen designed to detect cornea-specific proteins, we identified a novel protein that we named ferritoid that is found only in corneal cells. We have also shown that ferritoid binds to another protein, ferritin, and that this protein complex protects corneal DNA from UV damage. Our finding was unexpected because ferritoid was a previously undiscovered protein and because ferritin was previously thought to function solely in the storage of intracellular iron. The ability to bind to ferritoid and to prevent UV damage to DNA represents a unique and new function for ferritin.  Using a range of experimental approaches, including cell-based and molecular assays, and using the embryonic chicken as a model system, we are examining precisely how the ferritin-ferritoid complex is regulated, and how it works to prevent DNA damage. This project not only has important therapeutic implications, but also illustrates the value of taking an unbiased experimental approach like genetic screening when tackling historically intractable or inexplicable observations.

Kelly Beazley is a Ph.D. candidate in the Cell, Molecular and Developmental Biology Program. She is conducting her thesis research in the laboratory of Thomas Linsenmayer, Ph.D. Kelly earned her B.S. in Molecular and Cell Biology from Texas A&M University in 2001. While there, she worked in the laboratory of Thomas McKnight, Ph.D., studying telomerase regulation in Arabidopsis thaliana.

	Peter Cheslock

Peter Cheslock, Genetics
Meiosis is the process by which diploid organisms produce gametes that contain a single copy of each chromosome.  Errors in meiosis result in gametes with incorrect numbers of chromosomes.  Such imbalances are the leading cause of birth defects and are the cause of most spontaneous abortions.  An important way in which fidelity is maintained during meiosis involves recombination between homologous pairs of chromosomes.  Pairs that fail to recombine are the chromosomes most likely to segregate errantly in meiosis.  We have used a special strain of yeast that has an error-prone pair of chromosomes to study the mechanisms that control segregation of non-recombined chromosomes.   We have identified one protein, called Mad3, which is essential for the segregation of chromosomes that fail to recombine during meiosis.  This molecule acts as a timer to prolong a critical stage of meiosis called prophase to help insure that error-prone chromosomes have sufficient time to segregate properly.  We have shown that a human homolog called BubR1, can perform the same role in yeast.  Our results suggest deficiencies in BubR1 in people may be a primary contributor to the failures in meiotic segregation that lead to birth defects and spontaneous abortion.

Peter S. Cheslock is a Ph.D. student in the Genetics Program who is conducting his thesis work in the laboratory of Dean Dawson, Ph.D.   Peter graduated from Boston University with a B.S. in Biology in 2000, and formerly worked in the laboratory of Christine Li, Ph.D., at Boston University studying the function of a family of neuropeptide transmitters in C. elegans. 

	Sarah E. Poplawski

Sarah E. Poplawski, Biochemistry
Proteases represent a growing class of drug targets against a wide range of diseases; however, the identification of potent inhibitors that are also highly specific to their target has proven challenging.  Designing a drug that is not only pharmacologically inactive until it reaches the intended target, but becomes inactive again upon diffusing away should provide optimal efficacy and safety.  Such drugs have been termed “pro-soft drugs” but very few molecules with the potential to function in this way have been described and none have been tested for efficacy in vivo.  To resolve this, we have presented a general strategy to the design of pro-soft drugs for serine protease enzymes.  We have demonstrated the potential of the pro-soft drug concept for improving both efficacy and safety in vivo in the specific case of dipeptidyl peptidase IV, a validated target for the treatment of type 2 diabetes.  The results also indicate that the pro-soft drug concept will enable “tissue-specific” inhibition, allowing for inhibition of an enzyme in one type of cell or tissue without inhibiting the same enzyme elsewhere.

Sarah E. Poplawski is a Ph.D. student in the Biochemistry Program who is currently concluding her thesis work in the laboratory of William Bachovchin, Ph.D.  Previously, she earned her B.A. in Chemistry from Colby College in Waterville, ME in 2000.