Russ Carstens, MD studies the molecular mechanisms of alternative splicing. Investigation of splicing regulation by the epithelial-specific splicing factors Esrp1 and Esrp2 during development and disease. Regulation of genome-wide changes in splicing during the epithelial-mesenchymal transition (EMT).
Dr. Carstens' focus is investigation of alternative splicing, whereby a single gene transcript can generate numerous spliced mRNAs, thereby greatly expanding ribonomic and proteomic diversity. previous studies focused on alternative splicing of fibroblast growth factor receptor 2 (FGFR2) as a model system. Mutually exclusive splicing of two exons, IIIb and IIIc, gives rise to two functionally different receptors, FGFR2-IIIb and FGFR2-IIIc, in epithelial and mesenchymal cells, respectively. The exquisite cell type-specific expression of these epithelial or mesenchymal specific splice variants is essential during vertebrate development. Dr. Carstens identified Epithelial Splicing Proteins 1 and 2 (ESRP1 and ESRP2) in a genome-wide screen for FGFR2 splicing regulators. Subsequent work using RNA-Seq and other systems biology approaches has shown that the ESRPs regulate global programs of alternative splicing to enforce an epithelial cell specific splicing network. He is continuing further investigations into the molecular mechanisms by which the ESRPs regulate alternative splicing. To define the role that the Esrps play in mammalian development, he generated mice carrying conditional and/or germline knockout alleles for Esrp1 and Esrp2. Esrp1 knockout (KO) mice displayed bilateral cleft lip associated with cleft palate (CL/P), indicating that it is crucial for normal facial development. Mice with combined KO of both Esrp1 and Esrp2 displayed broader defects in organogenesis. Carstens Lab also determined that conditional ablation of Esrp1 and Esrp2 was associated with an epidermal barrier defect due in part to defects in epithelial cell adhesion and tight junction function. Ongoing studies with these mouse models are using a combination of genetics, developmental biology, and systems biology approaches to understand the mechanisms by which the Esrps function to maintain normal mammalian development and how disruption of Esrp function contributes to disease.
Lawrence Holzman, MD is an established and NIH funded laboratory investigator, well recognized for his investigations of mechanisms of cell signaling and also of podocyte biology, where he has contributed importantly to our understanding of the mechanisms that govern podocyte cytoskeletal architecture.
The Holzman lab studies the biochemistry and function of DLK, a member of the mixed lineage kinase family of MAPK kinase kinases. The laboratory initially discovered and cloned DLK and first demonstrated that DLK is a MAP3 kinase capable of activating the mitogen activated protein kinase family of JNK kinases. It showed that DLK is activated by insulin and in soon to be published work demonstrated that deletion of DLK in mice results in a phenotype of resistance to diet induced obesity and cell autonomous increased insulin sensitivity.
Dr. Holzman also investigates the biology of the glomerular podocyte, a unique epithelial cell that appears to play a
central role in most forms of glomerular disease. The octopus-like processes of the podocyte interdigitate and form specialized intercellular junctions that function as the kidney glomerular filter. The lab has been a leader in characterizing the molecular components of this intercellular junction and first established evidence to support the hypothesis that these junctional components participate in regulating podocyte morphology by modulating actin cytoskeletal dynamics. The lab has particularly focused on signaling functions of members of the cell adhesion molecules of the Nephrin family and has contributed seminal work on the atypical cadherin FAT1. As part of this work, the lab has developed a transgenic mouse strategy for examining the functional biology of proteins and their interactions specifically in the podocyte that is now used internationally.
Dr. Susztak's laboratory is aimed towards understanding the molecular pathways that govern chronic kidney disease development. The detailed work performed in Dr. Susztak's lab ranges from hypothesis generating high throughput translational research to fundamental and mechanistic studies.
The Susztak lab has carefully banked a large number of healthy and diseased human kidney tissue samples over the last 10 years, providing a basis for several combined genetic, epigenetic and genomic analyses. They hypothesize that integrative analysis of epigenetic and genetic settings in diseased cells can provide a rational basis for more accurately modeling the critical biological pathways involved in mediating the progressive phenotype in individual patients. They also predict that epigenomic integrative analysis can be used to determine the identity of chromatin and transcription factors that contribute mechanistically to aberrant transcriptional programming in chronic kidney disease, and that this information can be used for designing therapeutic strategies. The Susztak lab is specifically interested in defining cis-regulatory modules (promoters, enhancers and repressors) that govern the normal and altered epithelial phenotype in diseased kidneys. In addition, they use genetic approaches and the mouse as a model organism to test the role of candidate signaling molecules and regulatory pathways directly in vivo. The Cre/loxP and tet inducible transgenic technologies allow them to analyze the function of particular factors by deleting or overexpressing genes that encode them in specific cell types in the kidney. Specifically, we are working on determining the role of the Notch and Wnt/beta-catenin pathway in chronic kidney disease development, renal epithelial cell homeostasis, renal stem or progenitor cell function and differentiation. Their recent results highlight the role of embryonic programs in adult disease development.
Additional information about Dr. Susztak's research can be found here: https://www.med.upenn.edu/susztaklab/