- Structure-function studies of the three isoforms of nitric oxide synthase and their regulation in vivo;
- The role of mammalian peroxidases and nitric oxide synthases in promoting oxidative stress and their potential involvement in the disease state;
- Identification of potent inhibitors for mammalian peroxidases and scavenger to their final products
- The role of reactive oxygen and nitrogen species on oocyte aging.
These projects involve the utilization of state of the art analytical methods which include enzyme purification, expression cloning, site-directed mutagenesis, and methods to study protein spectroscopy including EPR, HPLC, stopped-flow and rapid quench.
View lab website
Our laboratory investigates signaling pathways that regulate cell invasion, proliferation and aptosis during early mammalian development. Studies of pre- and peri-implantation development using cultured rodent and non-human primate embryos, as well as human trophoblast and stem cell lines, address health issues related to infertility and obstetrical pathologies. In addition to receiving extramural research support from the National Institutes of Health (NIH), we operate within the NIH Division of Intramural Research and serve as the Peri-Implantation Development Laboratory for the NICHD Program in Reproductive and Adult Endocrinology.
Ongoing investigations examine how extracellular matrices, growth factors and oxygen concentrations unique to the mammalian conceptus regulate trophoblast survival and differentiation during blastocyst implantation and placentation. Much of the work has centered on intracellular signaling mediated by members of the epidermal growth factor (EGF) signaling system. For example, heparin-binding EGF-like growth factor is drastically reduced in preeclampsia, a disorder characterized by poor trophoblast survival and decreased invasion of maternal tissues. As key mechanisms regulating the EGF signaling system and trophoblast functions are resolved, they can be examined for possible roles in pregnancy failure or obstetrical disorders.
Phone: (313) 577-8910
View lab website
- The effects of prenatal exposure to abused drugs (cocaine, alcohol) and the benefit/harm of perinatal treatments for preterm infants (repeated antenatal corticosteroid, omega-3 fatty acids, aggressive phototherapy) using various neurological/sensory assessment tools in human infants and animal models;
- The effects of cancer chemotherapy drugs and chemoprotective agents on neurological/sensory function and development; and
- Hearing, neurological and MRI findings in craniosynostosis children (Apert, Crouzon, Pfeiffer syndromes)
Diagnostic auditory brainstem responses (ABRs) in neonates, children and animal models; prenatal/neonatal/postnatal database design and management; prenatal maternal recruitment and interviewing; neurodevelopmental toxicology and teratology assessments, multivariate statistical analyses; human and animal studies.
Deputy Director, Merrill Palmer Skillman Institute
Director, Fetal Alcohol Syndrome Treatment and Referral Service (FAStar); Obstetrics-Gynecology
Phone: (313) 664 -2503
Phone: (313) 577-8904
View lab website
Our laboratory investigates immunological pathways in normal and preterm birth in both human and animal models. Our objective is to develop novel diagnostic, therapeutic and preventive strategies to reduce adverse pregnancy outcomes, such as preterm birth. Current work focuses on the role of regulatory and effector T cells and the effect of the paternal fetal antigen during pregnancy and preterm birth. This work is carried out by using animal models (transgenic and knockout mice) and molecular biology techniques such as flow cytometry, microscopy, RT-PCR. These approaches allow the identification of phenotypes and intracellular components, such as DNA, messenger RNA for particular genes, specific surface receptors, intracellular proteins, and transient signaling events in living cells. The combination of these approaches allows the identification of etiological factors of preterm birth and other related pregnancy pathologies in humans, develop novel diagnostic, therapeutic and preventive strategies to reduce adverse pregnancy outcomes.
To achieve a Systems Biology level understanding of the genetic mechanism(s) that controls the selection of genes for development and differentiation.
Current Research Program:
We have directed our studies toward defining how gene loci are selected for expression by the mechanism termed potentiation, i.e., the opening of chromatin domains. Understanding the selective expression of our genome is fundamental to achieving the ability to reprogram our genome, the ultimate self-help therapeutic. My laboratory is using the endogenous and transgenic human and mouse protamine gene clusters as model systems of chromatin mediated differentiation. The epigenetic studies that we are pursuing extend from nuclear structure-histone modification to the role of non-coding RNAs as modulators of gene expression. Determining how these multiple levels of control interact and feedback to the genome to modulate chromatin structure and thus transcription is explored at the genome-wide systems level. We are currently extending these analyses to the level of the single cell. This data rich environment requires us to continually develop novel analysis tools while extending our computational capacity. The use of pipelining-grid computing and other strategies for high throughput bioinformatic analyses will help draw together our understanding of gene expression, chromatin structure and nuclear architect. We are beginning to uncover the complex set of processes that lead to successful conception and a healthy child. These incorporate both the genetic and epigenetic impactors of the fetal onset of adult disease, including the delivery of spermatozoon RNAs at fertilization. This population of RNAs may provide an essential component of early paternal genome reprogramming. By understanding the architectural system that regulates this mechanism we will have opened the door to using one’s own genome as a source of self-help therapeutics.
Interestingly SAPK upregulates the first essential trophoblast stem cell lineage, but blocks a later essential trophoblast lineage (Xie et al, manuscript in preparation). Similarly, stress induces an early essential lineage in embryonic stem cell differentiation and blocks a later essential lineage (Slater et al, manuscript in preparation). We call this “prioritized” differentiation and have observed that it occurs in progeny of both stem lineages in the implanting embryo (placental and embryonic stem cell lineages). The work has significant and profound implications for the mechanisms leading to the normal high loss of embryos soon after implantation and should lead to improvements in human in vitro fertilization and assisted reproductive technologies and to isolation and maintenance of higher quality embryonic stem cells. Knowledge of compensatory and prioritized differentiation will provide alternate high throughput toxicology tests that replace or reduce the need for gestational animal testing. Prioritized differentiation should provide biomarkers (Liu et al, 2009, Placenta, Xie et al., 2011, Int Rev Cell and Molec Biol) predicted by the enhanced ratio of early to late differentiated lineages during the adaptation to stress.
Laboratory techniques include: DNA methylation analyses (BS-Seq and Infinium) and histone modification analyses (ChIP-Seq and mDIP-Seq). His laboratory collaborates with the Applied Technology Genomics Core (ATGC) which has both low throughput and high throughput technologies to accommodate investigators needs, e.g. Solexa next-generation sequencing and Illumina Bead Arrays.
Professor Emeritus Faculty
Dr. Sacco is a Professor Emeritus in the Department of Obstetrics and Gynecology. He received a B.A. degree with a major in Biology from the University of Rochester (1966) and received his M.S. (1968) and Ph.D. (1971) degrees in Zoology (Reproductive Biology) from the University of Tennessee. He served as a post-doctoral fellow at the Institute for Cancer Research in Philadelphia (1971-1974) and has served on the faculty of Wayne State University School of Medicine from 1974- 2011.
His primary area of research centered on the field of immunocontraception and specifically, with target antigens associated with the zona pellucida. His early publications in this area were the first to attract interest in this particular approach to contraception vaccine development. In 1983, he became Director of the Assisted Reproductive Technologies (ART) Laboratories (In Vitro Fertilization Laboratory [IVF] and Andrology Laboratory) in the Department of Obstetrics and Gynecology where he oversaw the original construction and operation of these facilities for over 19 years. Other areas of research interest include fertilization, sperm-egg interactions and the assisted reproductive technologies.