The National Institutes of Health has awarded Wayne State University School of Medicine faculty member Zhibing Zhang, M.D., Ph.D., a new grant of $2,401,671 over five years to study defects in small organelles called cilia that can led to infertility and other disorders.
Dr. Zhang, an associate professor of Physiology and of Obstetrics and Gynecology, is the principal investigator on “Intraflagellar transport (IFT) and sperm formation,” funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
“Nearly one in seven couples is infertile, and up to half of these cases are caused by male infertility. Genetic factors contribute significantly to male infertility,” Dr. Zhang said. “However, most of these genetic factors are not clear. Mutations on IFT genes have been reported in infertile patients. Our studies will reveal novel genetic factors for male infertility. On the other side, findings from this research will also identify novel targets for the development of male-based contraceptives.”
His co-investigators on the project are Professor of Pharmaceutical Sciences Paul Stemmer, Ph.D., at the Proteomics Core Laboratory, and Associate Professor of Physics Christopher Kelly, Ph.D.
Cilia are small organelles that project from the cell surface. They play an indispensable role in organ development and function. Defects in cilia or cilia-related proteins cause various human pathologies, including male and female infertility, polycystic kidneys, hydrocephalus, vision, hearing loss and more, Dr. Zhang said.
Cilia are formed by an evolutionarily conserved mechanism, intraflagellar transport, or IFT. Through IFT, proteins and other components are transported to assemble functional cilia.
Twenty-two core IFT components have been identified to date.
“The role of IFT in somatic tissues has been extensively studied. However, little is known about its function in reproduction, particularly in the formation of sperm flagella, because inactivation of these IFT genes gives rise to embryonic lethality,” Dr. Zhang said. “Our laboratory is the first one in the world to use the cell/tissue-specific knockout strategy to study the role of IFT in mammalian reproduction, and we discovered that all IFT genes studied so far are essential for male fertility and sperm formation.”
Normal sperm motility is required for sperm to fertilize the eggs and is largely dependent on normal development of the sperm flagellum. However, the mechanisms that lead to proper targeting and assembly of proteins into the sperm flagellum are not fully understood.
Sperm flagella are specialized motile cilia. Compared to the cilia in the somatic cells, sperm flagella have accessory structures, including fibrous sheath, mitochondria sheath and outer dense fibers, accessory structures required for sperm motility.
“We discovered that IFT25, an IFT component, is very important for sperm accessory structure formation. This IFT is not required for cilia formation in somatic cells/tissues. We concluded that IFT25 plays a unique role in normal sperm formation/function by assembling the sperm accessory structures. Thus, this project aims to investigate the mechanism by which IFT25 regulates sperm formation and function,” he said.
The new project is related to a former project, in which the lab studied a protein complex present in a unique structure in male germ cells called the manchette. The structure is transient during male germ cell development. The structure is enriched in microtubules and F-actins and is believed to mediate transporting cargo proteins to the basal bodies for sperm formation through the process called intra-manchette transport.
“The basal body is the starting point for IFT and provides the template for cilia formation,” Dr. Zhang said. “So, IFT is the extension of IMT, and the two transport systems are functionally connected.”
The award number for this National Institutes of Health grant is R01HD105944.