Development of Highly Innovative Tools and Technology for Analysis of Single Cells (STTR) (R41/R42)

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 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 dataset 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).   

NCI

Tumors are highly heterogeneous at the cellular, molecular, and genetic levels. Through this FOA, the NCI is especially interested in applications for 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, high throughput technologies for isolation and characterization of DNA and RNA from individual cells either in situ or in clinically relevant samples.

NCATS

NCATS intends to fund applications under this funding announcement that meet its mission. For a description of the NCATS SBIR/STTR research priorities, please refer to http://ncats.nih.gov/smallbusiness/priorities.

NIDCR

NIDCR supports research and research training to improve dental, oral and craniofacial (DOC) health.  For a full spectrum of our research interests, please consult NIDCR Strategic Plan 2014-2019.  Relevant to this FOA, high priority will be placed on the application of tools and technologies to differentiate benign, malignant and metastasizing oral or salivary gland cancer cells, detect malignant transformation of oral epithelial cell including human papillomavirus (HPV)-positive and HPV-negative status, identify and characterize stem/progenitor cells for DOC tissue regeneration, and trace cell fates and lineages of DOC cells along developmental, degeneration and regeneration pathways.

NIDDK

NIDDK is interested in applications for the development of novel tools/technologies with single cell resolution able to generate precise data in the following areas: 

a)Better understanding of pancreatic islet function and dysfunction through the identification of local alterations or cellular signatures in the islet and extra-islet environment that are associated with islet cell plasticity, diabetes pathogenesis, progression or response to treatment and may lead to the discovery of novel cellular or molecular therapeutic targets; study of cell subtypes in other tissues/organs involved in the development and progression of diabetes and other endocrine diseases and their complications. These include analysis of cell diversity of the immune system, adipose tissue, muscle, liver, gut, nervous system and their interactions to better understand initiation, progression and/or heterogeneity of the disease in humans. 

b) Isolating and interrogating single cells from normal or diseased tissues of the alimentary gastrointestinal tract, liver, biliary system, and exocrine pancreas.

c) Isolating and interrogating single cells from normal or diseased kidney, lower urinary tract, including the urinary bladder, prostate, or hematopoietic stem cell niche, or techniques to be used by the Kidney Precision Medicine Project consortium.

Relevant proposals may include but are not limited to the development or improvement of multidimensional single cell imaging, single cell mass cytometry protocols and high throughput technologies for the multi-omics exploration of individual cells either in situ or in clinically relevant samples. For a description of disease areas relevant to the NIDDK, please refer to https://www.niddk.nih.gov/research-funding/research-programs/Pages/default.aspx.

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. 

NCCIH

National Center for Complementary and Integrative Health (NCCIH) is interested in supporting research that will develop highly innovative tools and technology for analysis of single cells in response to natural products, their metabolic derivatives, probiotics, or prebiotics at genetic/genomic, epigenetic/epigenomic, metabolomic, or other molecular and cellular levels. 

See Section VIII. Other Information for award authorities and regulations.