SBIR-STTR Award

There is a paradigm shift in testing and modeling of chemical toxicity. Current toxicology calls for human-cell- based (vs. animal-based), evidence-based, and Omics-based assays. Mesenchymal stem cells (MSC) play important roles in the maintenance and repair of various tissues, including bone, cartilage, and muscle. MSCs are also found in circulating blood and participate in the wound-healing process. Therefore, MSC is arguably one of the most physiologically relevant adult stem cells for chemical toxicology. In response to RFA-ES-13- 003, Newomics Inc. proposes to develop high-throughput Omics-based assays to evaluate the effects of chemical toxicants on proliferation and differentiation of human MSC. The core technology platform will be based on Newomics' breakthrough silicon-microfluidic-chip, the multinozzle emitter array chip (MEA chip), which enables nanoflow liquid chromatography-electrospray ionization mass spectrometry (nanoLC-ESI/MS)- based, high-sensitivity, high-throughput, and multiplex measurements of multiclass analytes (peptides, proteins, and metabolites) at the Omics level, from small volumes of samples. The project will also take advantage of our extensive experience in the characterization of human MSC and mechanistic studies of their responses to genotoxic stresses such as ionizing radiation and chemical toxicants such as hydrogen peroxide. In this Phase I project, we will demonstrate a robust and universal two-stage workflow for Omics-based and high-content screening of chemical toxicity using human MSC. In Aim 1, we will develop phenotypic assays to prioritize the conditions for the focused follow-up Omics-based assays. In Aim 2, we will perform high- throughput proteomic and metabolomic analyses of MSC before and after chemical treatments, and the associated medium supernatants from each well on the 96-well or 384-well plates used for the quantitative high-throughput screening (qHTS). We will perform bioinformatics analysis and delineate the pathways and networks responsible for the chemical toxicity to MSC. If successful, Newomics' MEA chip may become a universal platform for Omics-based chemical toxicology using stem cells.

Public Health Relevance Statement:


Public Health Relevance:
Cutting-edge technologies enable breakthroughs in biomedical research. Developments of innovative Omics- based assays for screening chemical toxicity on stem cells will improve risk assessment of personal exposure to environmental toxins, and thereby providing new strategies for public health.

NIH Spending Category:
Biotechnology; Regenerative Medicine; Stem Cell Research

Project Terms:
Acute Toxicity Tests; adult stem cell; Aftercare; Albumins; Alkaline Phosphatase; Animals; base; Bioinformatics; Biological Assay; Biomedical Research; Blood; bone; Bone Marrow; Calcium; Cartilage; Cell Proliferation; Cells; Chemical Models; Chemicals; Collaborations; cytotoxicity; Development; environmental chemical; Evaluation; evidence base; experience; Exposure to; follow-up; Foundations; Genotoxic Stress; Goals; Hepatotoxicity; high throughput screening; Human; Hydrogen Peroxide; improved; In Vitro; in vivo Model; Individual; Indocyanine Green; innovation; Ionizing radiation; Libraries; Liquid Chromatography; Maintenance; Measurement; Mesenchymal Stem Cells; metabolomics; Microfluidics; Molecular; Muscle; Neutral Red; novel; Osteogenesis; osteogenic; Pathway interactions; Peptides; Performance; Phase; Play; population based; Process; programs; protein metabolite; Proteome; Proteomics; Protocols documentation; public health medicine (field); public health relevance; Reagent; repaired; Research Personnel; response; Risk Assessment; Role; Sampling; scale up; screening; Sensitivity and Specificity; Silicon; Small Business Innovation Research Grant; Solid; Spectrometry, Mass, Electrospray Ionization; Staging; Staining method; Stains; Statistical Study; Stem cells; Stromal Cells; System; Technology; Testing; Time; Tissues; Toxic effect; Toxic Environmental Substances; toxicant; Toxicology; trend; United States National Institutes of Health; uptake; Variant; Variation (Genetics); Wound Healing

There is a paradigm shift in testing and modeling of chemical toxicity. Current toxicology calls for cell-based (vs. animal-based), evidence-based, and Omics-based assays. Mesenchymal stem cells (MSC) play important roles in the maintenance and repair of various tissues, including bone, cartilage, and muscle. MSCs are also found in circulating blood and participate in the wound-healing process. Therefore, MSC is arguably one of the most physiologically relevant adult stem cells for chemical toxicology. In response to RFA-ES-15-006, Newomics Inc. proposes this SBIR Phase II project to complete development of its product, high-throughput Omics-based assays to evaluate the effects of chemical toxicants on proliferation and differentiation of stem cells. The Phase II project is buil upon the extremely promising results generated from our Phase I project. In Phase I, we have demonstrated a robust and universal two-stage workflow for Omics-based and high-throughput screening of chemical toxicity using human MSCs. We have also discovered several pathways and networks for mechanistic understanding of chemical toxicity on MSCs. In Phase II, we will scale up our toxicity assays for MSCs using the Tox21 10k library, develop Omics-chips and validate their applications in Omics-based assays for chemical toxicity, and provide a toolkit for screening the effects of chemical toxicants on cell differentiation. Once developed, our platforms and solutions may be utilized for chemical toxicity studies of other types of stem cells such as ESCs and iPSCs, to help prioritize chemicals for in-depth toxicological evaluation, and to even help develop new intervention strategies for mitigating chemical toxicity, thereby contributing to public health.

Public Health Relevance Statement:


Public Health Relevance:
Cutting-edge technologies enable breakthroughs in biomedical research. Developments of mass spectrometry-based microchip platforms for screening chemical toxicity using stem cells will help prioritize chemicals for in-depth toxicological evaluation, thereby providing new strategies for impacting public health.

Project Terms:
adult stem cell; Animals; Automation; Back; base; Biochemical; Bioinformatics; Biological Assay; Biomedical Research; Blood; bone; Businesses; Cartilage; Cell Differentiation process; Cell Proliferation; Cells; Chemical Models; Chemical Structure; Chemicals; Collaborations; commercialization; Computer software; Development; Evaluation; evidence base; Harvest; high throughput screening; Human; in vivo; induced pluripotent stem cell; industry partner; Intervention; Journals; Libraries; Liquid Chromatography; Maintenance; Marketing; mass spectrometer; Mass Spectrum Analysis; Measurable; meetings; Mesenchymal Stem Cells; metabolomics; microchip; Microfluidics; Muscle; next generation; novel; osteogenic; Paper; Pathway interactions; Phase; Play; Preclinical Drug Evaluation; Process; Proteins; Proteomics; public health medicine (field); public health relevance; Publishing; repaired; Research; research and development; Resistance; response; Role; scale up; screening; Silicon; Small Business Innovation Research Grant; small molecule; Solutions; Specific qualifier value; Spectrometry, Mass, Electrospray Ionization; Staging; stem cell differentiation; Stem cells; Technology; Testing; Tissues; Toxic effect; toxicant; Toxicology; United States National Institutes of Health; Validation; Work; Wound Healing