he purpose of this Funding Opportunity Announcement (FOA) is to establish state-of-the-art Tissue Mapping Centers (TMCs) within the Cellular Senescence Network (SenNet) to build an atlas of cellular senescence in mice. The overarching goal of the SenNet consortium is to identify and functionally characterize, at single-cell resolution, the heterogeneity of senescent cells across multiple human tissues in health and lifespan. A previous FOA (RFA-RM-21-008) established the TMCs to generate data and build maps in humans. The purpose of this FOA is to solicit applications that complement the human effort by generating an atlas of cell senescence in mice that will help inform the ongoing effort in humans and serve as a blueprint for future translational research performed in mice. Through collaborative efforts, the murine component of the consortium will generate a multimodal, multidimensional atlas of senescent cells in various murine tissues (tissue choices will be predominantly dictated by the corresponding human tissues already in use within the SenNet consortium); develop innovative tools and technologies to identify and characterize senescent cells; and aggregate data across the Network into a searchable atlas of murine Cellular Senescence. The TMCs solicited through this RFA will create high-resolution, high-content, multiscale biomarkers and maps of cellular senescence across the murine lifespan, to generate a murine-specific companion to the human Senescence atlas. The mouse component of the SenNet consortium will initially focus on healthy murine tissues (modified disease models are not allowed) derived from both inbred and outbred mouse strains that are commonly used and have demonstrated value in pre-clinical research. TMCs will be expected to integrate and optimize all parts of the data generation pipeline, from tissue collection and preservation through analyses at organ-, tissue- and single-cell- level using omics, imaging and other approaches, to data integration, analysis and interpretation.
Companion Funding Opportunities:
RFA-RM-22-004 , UG3/ UH3 Phase 1 Exploratory/Developmental Cooperative Agreement/Exploratory/Developmental Cooperative Agreement Phase II
RFA-RM-22-005 , UG3/ UH3 Phase 1 Exploratory/Developmental Cooperative Agreement/Exploratory/Developmental Cooperative Agreement Phase II
Cellular senescence was initially described by Hayflick and Morehead in 1961, but remained relatively understudied for the next 3 decades, as senescence was originally thought to be an in vitro phenomenon. However, starting in 2001, work by multiple groups showed that senescent cells can negatively affect their local tissue environments through multiple pathways including the Senescence-Associated Secretory Phenotype, or SASP. The subsequent finding that these cells are found in vivo and are more abundant than previously thought led to the development of genetic and pharmacologic methods to manipulate or remove senescent cells. Importantly, removal of senescent cells in adult mice led to significant improvements in both healthspan and lifespan.
These advancements have resulted in significant interest in the development of senolytics, drugs that can preferentially eliminate senescent cells. However, several issues need resolution before interventions to remove senescent cells are tested in humans. For example, while excessive accumulation of senescent cells is associated with deleterious late-life effects including accelerated aging and increased susceptibility to chronic diseases such as atherosclerosis, cancer, cardiac dysfunction, kidney dysfunction, neurodegeneration, pulmonary fibrosis and many others, senescent cells also serve beneficial roles during tissue remodeling in embryogenesis, as well as during parturition and wound healing. In addition, their role as a tumor protection mechanism is also well established.
Progress in the past few years has also indicated a large heterogeneity in senescent cells’ characteristics depending on the inducing agent or pathway, the cell type and tissue, and life stage. Similarly, the SASP appears as heterogeneous as the cells from which it is derived. Therefore, understanding the mechanisms that distinguish beneficial from deleterious senescence and the heterogeneity underlying senescent cell states are critical knowledge gaps. As the science progresses, it is clear that a “one size fits all” for the development of senolytics that only remove deleterious cells without touching beneficial senescent cells is not realistic, and a detailed characterization of senescent cell states and their associated SASP is an urgent need.
To address the knowledge gaps noted above, the NIH supported the creation of a Cellular Senescence Network (SenNet), charged with identifying biomarkers and constructing tissue maps and atlases that describe multidimensional parameters of senescence across diverse tissue environments at molecular, cellular, and morphological levels and over longitudinal time frames. While the initial RFAs were focused only on human tissues, mice are important preclinical / translational models for biomedical research, and it is therefore important to identify the similarities and differences in cellular senescence between mice and humans. Characterizing cellular senescence in murine models commonly used in biomedical research is the primary focus of the current RFA. The SenNet effort builds upon and extends existing single cell tissue mapping efforts including the Human Tumor Atlas Network,Human Biomolecular Atlas Program, and Human Cell Atlas. Together with the SenNet program, these efforts will continue to generate important resources for the scientific community that will inform future research and, ultimately, clinical decision-making.
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Filed Under: Funding Opportunities