Richburg, John H., Ph.D.
Division Head, Associate Professor
Wm. I. Dismukes Fellow
PHR 5.218C
512-471-4736
john_richburg@mail.utexas.edu

The focus of our research program is on characterizing the molecular and cellular mechanisms that initiate testicular germ cells to undergo apoptosis (programmed cell death) after injury by environmental or chemotherapeutic agents. One research project uses mono-(2-ethylhexyl) phthalate (MEHP), a widely characterized Sertoli cell toxicant, as the primary model agent to study the mechanisms initiating germ cells to undergo apoptosis. In addition, a recent project in the laboratory is targeted toward revealing the mechanisms that confer an exquisite sensitivity of germ cells to undergo apoptosis after exposure to the chemotherapeutic agent cisplatin.

Previous work in the laboratory has established that the Fas (CD95)-signaling pathway participates in the initiation of testicular germ cell apoptosis after MEHP-induced Sertoli cell injury. However, we have shown that germ cells from B6.SMNC3H-Fasgld,gld (gld) mice that express a dysfunctional form of FasL still undergo significant apoptosis, albeit at a lower incidence than seen in B6 mice (wild type), following mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury. Although these observations strongly indicate the participation of Fas in the initiation of germ cell apoptosis after MEHP exposure, they also reveal a contribution of a Fas-independent apoptosis-related signaling mechanism. Current investigations are target to evaluate the participation of other 3death receptors2 in the initiation of germ cell apoptosis such as TRAIL-R1 (DR4); TRAIL-R2 (DR5, TRICK2, KILLER) and the newly identified member DR6. It is postulated that one or more of these receptors may play a role in the regulation of germ cell apoptosis under physiological conditions and, perhaps, after toxicant-induced testicular injury.

A recent project in the laboratory is targeted to characterize the apoptotic signaling pathway(s) responsible for conferring the high sensitivity of testicular germ cells to death after treatment with the prototypical chemotherapeutic agent cisplatin. Germ cell tumors are the most common types of testicular cancer in men 15 to 34 years of age in the United States. Testicular germ cell tumors are extremely sensitive to elimination by chemotherapeutics. This is reflected by the greater than 80% cure rate of these tumors. However, the reason for their sensitivity to these agents is not well understood. Recent findings from our laboratory suggest the importance of factors secreted from the mitochondria in the initiation of cell apoptosis. The working hypothesis of this research project is that cisplatin exposure results in the secretion of pro-apoptotic factors from the mitochondria of germ cells and is responsible for conferring the enhanced sensitivity of these cells to apoptosis. The long-term goal of this research is to gain information to allow for a rationale design of novel therapeutic agents that may more efficiently exploit the sensitivity of germ cells to death by apoptosis while limiting the deleterious side effects on testis function and preserving fertility in men undergoing chemotherapy.