The long-term goals of our research are to understand molecular mechanisms of transcriptional regulation of the small leucine-rich proteoglycans (SLRP). Experimental evidence demonstrates that these genes share common functions - they regulate collagen fibrillogenesis and modulate cellular growth. Many functionally related genes, such as HOX and erythroid-specific genes, often are organized in clusters and their expression is precisely regulated in time and space. The SLRPs also are organized in clusters on human chromosomes 1, 9 and 12, but the physiological significance of this arrangement is unclear. Our research will determine whether the SLRP gene clusters on human chromosomes 9 and 12 are subject to transcriptional co-regulation, and it is based on our findings that: 1. Twelve of 13 SLRPs have at least one conserved HOX-Runx module in their promoter, exon 1, or intron 1; 2. Biglycan (Bng) and chondroadherin (Chad) are suppressed in the absence of mimecan. We hypothesize that the common HOX-Runx module is a basis for a co-regulated expression of the SLRPs, and that evidence for a locus control region, similar to that of beta-globin gene cluster, will be found on both chromosomes. A second goal of our research is to understand why multiple mimecan mRNA transcripts coding for the same, unchanged protein are synthesized in the same tissue. We hypothesize that mimecan splice forms also have functions other than coding for the same protein. Information generated from our studies will be of enormous value for developing molecular therapies aimed at correction of abnormal gene expression and/or erroneous splicing. Such studies also are required for improving the function of biomaterials used in clinics and for generation of tissues for transplantation.
Chromatography, peptide mapping and recombinant DNA methods for structural identification of abnormal hemoglobins; Clinical and genetic aspects of human leukemias and lymphomas.
Cornea, Eye, Extracellular Matrix Protein, Inflamation, Molecular Biology, Protein Interactions, Signal Transduction, Transcriptional and Posttranscriptional Regulation
Knowledge of how an extracellular matrix protein is regulated and works may suggest new therapeutic targets for diseases caused by tumors, trauma, inflammation and aging.
The keratan sulfate-containing proteoglycans (KSPGs) of the cornea have been recognized as important molecules that regulate collagen fibrillogenesis, influence corneal hydration and affect cellular growth. Mimecan, a major corneal KSPG, is expressed in various connective tissues and almost all parts of the vertebrate eye. Only in cornea mimecan carry unique keratan sulfate glycosaminoglycan chain(s). Targeted disruption of the mimecan gene in the mouse results in abnormal collagen fibrils in cornea and skin, and changed expression of several genes encoding calcium-sensitive components of the cytoskeleton, inhibitors of angiogenesis, G-protein-coupled signaling molecules, and extracellular matrix components, including two small leucine-rich repeat family members, biglycan and chondroadherin. Transcription factors that are involved in cellular stress response, such as p53 and USF, and high glucose affect mimecan expression. Molecular mechanisms by which mimecan exerts its biological effects are unknown. In our future research a hypothesis that mimecan plays roles in regulation of growth and stress responses of the cells residing in the cornea, as well as functions of macrophages will be tested.
