Development of Highly Innovative Tools and Technology for Analysis of Single Cells (SBIR) (R43/R44 Clinical Trial Not Allowed)

Background Single cell analysis has recently become an active area of research to uncover fundamental biological principles behind cell diversity, which are often masked and not amenable to the population analysis of cells. The past several years have witnessed a rapid advancement in the development of single cell technologies and analysis methods. Multiple single cell "-omics" approaches are emerging that provide unprecedented high resolution of molecular signatures of a cell. The ability to measure genomic, epigenomic, transcriptomic, and metabolic status in individual cells are expected to provide new insight into molecular pathways in health and disease. In addition, powerful technologies are being developed to isolate and analyze rare cells from a heterogeneous population and to examine distinct cellular states in complex tissue environments. Several NIH programs have recently strengthened the support of single cell research and technology development, including the NIH Common Fund Single Cell Analysis Program (SCAP) (http://commonfund.nih.gov/singlecell/) and BRAIN initiative (http://www.braininitiative.nih.gov). This Funding Opportunity Announcement (FOA) intends to add the support and address key roadblocks in single cell analysis research by facilitating the commercialization of the innovative single cell analysis technologies and tools. A goal is to accelerate the development and translation of the cutting-edge single cell analysis approaches. The NIH expects that the commercialization of the advanced single cell technologies and tools will help expedite biomedical research and advance precision medicine to the cellular level by generating new knowledge on cellular heterogeneity, cellular organization and communication rules, as well as emergent properties. Here, NIH calls on the small business community to generate highly innovative technologies and tools that will assist with this goal. Objectives This FOA encourages applications to develop next-generation technologies and tools to better define cell heterogeneity and organizational rules. The innovative approaches should provide new analytical measures and manipulations of: cellular contents, structure, and activity at the single cell level significantly beyond those currently available. The objectives are to accelerate the development and translation of promising concepts by focusing on overcoming technical challenges, building prototype systems, and generating novel tools toward commercialization. This FOA seeks to support innovative projects that will result in robust tools and approaches widely adoptable and usable by the research community through the marketplace. Toward this end, applications that draw upon diverse expertise from both within and outside (e.g., engineering, physics, chemistry, computation) of biology are of particular interest. To the extent that it is useful in combining different types of expertise, applications with multiple Program Directors/Principal Investigators are encouraged (See http://grants.nih.gov/grants/multi_PI/). Applications can propose high-impact technologies that include, but are not limited to: ? Devices and reagents to perform novel total (i.e.,"-omic") molecular and/or functional analyses of a wide variety of cell types (e.g., imaging-based spatial “-omics”, microdroplet-based high throughput “-omics”). ? Combinations of tools for multiplex analysis and/or manipulation of single cells to maximize data content over many parameters (e.g., gene expression, protein interaction, metabolic states, electrochemical dynamics, signal secretion/reception/transduction, cell adhesive properties, intercellular communication, cytoarchitectonic or migratory changes). ? Tools that provide significant advances in assay sensitivity, selectivity, scalability, or spatiotemporal resolution of molecules/structures/activities of single cells in situ. ? Automated manipulation or precise perturbation for scalable analysis of single cells, including parallel readouts in multiple cells and/or speed of processing. ? Tools and technologies that enable and transform single cell analysis in clinical tissue biopsies. ? Systems-level single cell data set analysis or modeling, including computational approaches, in the context of tissues or whole organisms. Research designs should focus on the development and validation of technologies and tools in the context of a variety of biological experiments, such as: ? Identification of spatiotemporal transitions in cellular states (e.g., progenitor lineage determination, cellular aging, clonal selection and evolution, asymmetric division, cell specification, cell reprogramming). ? Detection or isolation of rare cells in a population (e.g., stem cells, tumor-initiating or metastatic cells, drug resistant cells). ? Elucidation of the cell molecular signatures at levels including DNA, RNA, protein, or metabolite or functional consequences of molecular changes (e.g., genomic stability, epigenetic regulation, RNA modification or editing, protein modification or interaction, lipid metabolism). ? Characterization of heterogeneous cell responses to environmental changes (e.g., homeostatic perturbation, modulation of niche/microenvironment, morphogens or cell-to-cell signaling, toxic exposure, experience-dependent plasticity, host cell responses to infectious, immunological or allergic challenges). Although applications will not be restricted to a particular type of technology, NIH is especially interested in applications to develop next-generation approaches that can or have the potential to distinguish heterogeneous states among cells in situ or in clinically relevant samples. Well-established biological assay(s) and positive control experiments should be included for proof-of-concept testing and validation of the innovative technologies and tools. Potential pitfalls of the experimental measurements must be clearly discussed and minimized accordingly. Single cell analysis methods should address signal-to-noise issue and strive to reduce technical noise by optimizing experimental processes. Applicants are expected to evaluate and interpret “noise” of the measurements, which can have both technical and biological origins. Methods and analyses should take into account the sample source variability and the inherently dynamic nature of biological processes such as cell cycle and developmental plasticity, which may complicate the interpretation of the measurements. It is important to emphasize that the topics listed above are only meant to be illustrative, and not meant to be a comprehensive list of appropriate topics, nor exclusive of other appropriate topics. Applications may propose projects that are highly innovative or that are enhancements of current approaches. In either case, studies must significantly advance the current state of the art of single cell analysis and have commercial potential. Submitted applications should be aligned with the research priorities of at least one of the participating ICs (see below and Part 1). Potential applicants are strongly encouraged to contact Scientific/Research Contact(s)before submitting an application. All applications must explicitly address considerations detailed in Section IV.2 - Application and Submission Information. Interests of the Institutes and Centers NIMH The NIMH intends to support the development of single cell technologies to advance the mission of the Institute as described in the NIMH Strategic Plan. In particular the NIMH is interested in the next-generation approaches that can or have the potential to distinguish heterogeneous states of brain cells in mammalian and human brain samples (e.g.,NIH NeuroBioBank). NCATS NCATS intends to fund applications under this FOA that meet its mission. For a description of the NCATS SBIR/STTR research priorities, please refer to http://ncats.nih.gov/smallbusiness/priorities. NIDA NIDA supports research to understand, prevent, and treat substance use disorders and mitigate their consequences to public health. For this FOA, NIDA encourages basic and/or clinical collaborative research to promote the understanding of mechanisms of neuronal differentiation, neural circuit formation and modulation, synaptic formation, trimming and activities, as well as related events of brain development pertinent to substances of abuse, including but not limited to nicotine, amphetamine, cocaine, opiates, barbiturates, cannabinoids, and hallucinogens. Specifically, for this FOA, NIDA is interested in the identification of genetic and epigenetic effects on the development and function of the nervous system, as well as novel approaches to elucidate the processes and genetic mechanisms involved in the development of brain regions, neural circuits, and neurotransmitter systems mediating the addictive properties of drugs of abuse to inform future prevention and treatment of substance use disorders. Please note: NIDA does not support Phase IIB applications, or Phase IIB research, for this announcement. NIGMS NIGMS supports basic biomedical research and research training that contributes to the understanding of fundamental cellular and physiological principles, and specific clinical areas (i.e., clinical pharmacology, trauma and burn injury, sepsis, wound healing, and anesthesiology) contained within the mission of NIGMS. NIEHS NIEHS supports research on how the environment affects people in order to promote healthier lives. For this FOA, NIEHS is interested in tools and technologies to detect responses to environmental stressors in heterogeneous populations of cells, approaches to detect effects of environmental stress on germ cells, and technologies to isolate or detect effects in stem or progenitor cells. Please see the NIEHS Program Descriptions and Research Topics for more detailed information. NEI The NEI supports biomedical research and research training to understand the visual system, a major component of the human brain. Loss of neurons or various cell types in the retina or the brain can cause visual impairment. NEI is interested in applications for the development of novel tools/technologies with single cell resolution that can improve our understanding in all cell types in the visual system, and how they connect with each other. For a description of the NEI SBIR/STTR research priorities, please refer to https://nei.nih.gov/funding/smallbusiness_nei NHGRI Through this FOA, NHGRI is especially interested in supporting applications that address: (1) measurement of chromatin features, and simultaneous measurement of chromatin features and transcriptomic responses in human tissue in high throughput, (2) spatially resolved genomic measurements in situ, (3) development of robust analytical methods for integration of diverse genomic data modalities, QA/QC, normalization and other methods that improve analytical pipelines for genomics. NCI Tumors are highly heterogeneous at the cellular, molecular, and genetic levels. Through this FOA, the NCI is especially interested in applications requesting support for research on novel tools/technologies that enable the characterization of this heterogeneity among cells in situ or in clinically relevant samples and for clinically testing drug combinations and resistance with minimal invasiveness. These tools/ technologies include but are not limited to multidimensional single cell imaging, single cell mass cytometry, and high throughput technologies for isolation and characterization of DNA and RNA from individual cells either in situ or in clinically relevant samples.