Epigenetic modifications of DNA and histones are stable encryption systems essential for life. For example, the importance of DNA methylation is underscored by the consequences of its mis-regulation, which include defects in tissue homeostasis, chronic disease and accelerated aging; thus epigenetics broadly impacts human health. The information stored in the distribution of 5-methyl-cytosine is flexible, stable and heritable after cell division; however, unlike genetic mutation, epigenetic changes may be pharmacologically reversed. The goal of this research is to commercialize products that will be used to develop a better understanding of the evolution of epigenetic miscues in disease and to discover new epi-therapuetics. We propose a series of fluorochrome- based reporter kits with content rich protocols that examine epigenetic reprogramming (imprinting) and DNA methylation maintenance in human disease. Such products will see applications in discovery of treatment strategies in cancer, Parkinson's disease, Inflammatory Bowel Disease, as well as developing an understanding behind the newly discovered epigenomic clock (aging) in human and non-human primates. This will promote new therapeutic inroads by identifying druggable targets, and dissecting pathway proteins regulating DNA methylation aging and chronic disease. The commercial products are based on a model system that uses endogenous GFP/RFP reporters and homing endonuclease mediated damage-repair by homologous and non- homologous routes; both pathways induce methylation revision at repaired DNA segments and yield new epialleles. Because this is a cell based imprinting, two important benefits will be realized. First high resolution, single cell epigenetics will be possible; and second, a single cell can be tracked into future generations by live imaging. The company will offer a selection of reporters (expression vectors, ad hoc engineered cell lines and kits) to examine alterations in methylation revisions and repair in defined disease models. This will allow an innovative screening system for novel epi- therapeutics in a cellular context. In sum, this proposal translates the basic information on DNA methylation maintenance into a flexible system that can be used to monitor, manipulate and dissect the process in somatic cells and animal models. These products will be used in diverse areas of biomedical research (studies on environmental connectivity to epigenetic circuitry, neurologic, inflammatory, metabolic diseases, epigenetic mutagens, chronic multi-trait diseases, nutrition, aging, etc). For the Phase II SBIR a new bioinformatic algorithm i described that interprets epiallele evolution for application in clinical and personalized medicine
Public Health Relevance Statement: Public Health Relevance: The development of targeted cancer therapies would be a clear advance in the treatment of cancer. Since cancer costs in the U.S. are well over $250 billion per annum, it makes both medical and economic sense to invest in new pharmaceutical discovery technologies. A large market share of agents is dedicated to genotoxic strategies that include DNA binding proteins such a DNA methylases. Mechanism and computation based drug discovery will yield new agents that can selectively target and kill cancer cells. This SBIR projec directly addresses this important public health issue. The project is also linked to a profitable research diagnostics business that exports US made products and contributes to job creation and economic growth in this country through a global distributor network. The projected market universe for epi- therapeutics alone is predicted to be $8-10 billion by 2017.
Project Terms: Acute; acute toxicity; Address; Aging; aging nutrition; Algorithms; Animal Model; Animals; Area; base; Binding; Bioinformatics; Biological Assay; Biological Models; Biomedical Research; Businesses; cancer cell; cancer therapy; Cell Cycle; Cell division; Cell Line; Cell Maintenance; Cell model; Cell Nucleus; Cells; Chronic; Chronic Disease; Clinical Medicine; Complement; Complex; cost; Country; Crohn's disease; Cytosine; Data; Defect; design; Development; Diagnostics Research; Disease; Disease model; DNA; DNA Methylation; DNA Modification Process; DNA Repair; DNA Sequence Alteration; DNA-Binding Proteins; drug discovery; Economics; encryption; endonuclease; Engineering; epigenetic drug; Epigenetic Process; epigenome; epigenomics; Event; Evolution; expression vector; Failure; FDA approved; flexibility; Fluorochrome; Future; Future Generations; Gene Expression; Gene Silencing; Gene Silencing Pathway; Generations; Genes; Goals; Grant; Growth; Health; Histones; Homeostasis; Homing; Human; human disease; Human Pathology; Image; imprint; In Vitro; in vivo; Industry; Inflammatory; Inflammatory Bowel Diseases; Inheritance Patterns; innovation; insight; Killings; Knowledge; Life; Link; live cell imaging; Maintenance; Malignant Neoplasms; Marketing; Mediating; Medical Economics; Metabolic Diseases; Methylation; Methyltransferase; MicroRNAs; Modeling; Monitor; Mutagens; Mutation; Natural Product Drug; nervous system disorder; Neurologic; New Agents; New Territories; nonhuman primate; novel; novel strategies; novel therapeutics; Nuclear; Nucleosides; Occupations; Organism; Parkinson Disease; Pathway interactions; Performance; personalized medicine; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Physiological; Process; Protein Isoforms; Proteins; Protocols documentation; prototype; Public Health; Publishing; Reagent; Regulation; repaired; Reporter; Research; research and development; Research Personnel; research study; Resolution; Role; Route; S Phase; screening; Series; Small Business Innovation Research Grant; small molecule; Solid; Somatic Cell; Specificity; Stem cells; Sum; System; targeted cancer therapy; Technology; Therapeutic; Time; Tissues; Toxic effect; trait; Translating; treatment strategy; Tumor Suppressor Genes; uptake; Validation
