To measure human biology, we need to understand the mysteries of the cell and how cells interact within and as systems. Metabolism is a complex and highly interconnected process, with many different pathways that feed into one another. It encompasses various biochemical processes, chemical reactions, and conversions that transform one form of energy into another, regulating the rate of nutrient uptake from the immediate environment to essentially maintain the living state of a cell or an organism. Metabolic physiology goes beyond studying metabolic pathways and requires consideration of dynamic processes that cross time and space scales. To clarify metabolism and its connection to diseases requires investigating how metabolism is integrated within molecules, organelles, cells, tissues, and organisms, further suggesting that multiple experimental and technological approaches are needed to measure metabolism in action. Mapping, measuring, and integrating metabolism across scales and systems is a path to understanding various facets of human physiology and addressing many common and rare diseases.
Scope and Project Specifications
The Chan Zuckerberg Initiative (CZI) seeks to support two-year collaborative research projects focused on measuring metabolism across organelles and cells. The ability to characterize temporally and spatially the broad molecular profiles, heterogeneity, and phenotypic diversity of organelles and cells and how they interact within and as systems are key to measuring human biology, understanding disease mechanisms, and finding treatments and cures. This Request for Applications (RFA) aims to accelerate innovative discoveries in metabolism and metabolic physiology in health and disease. Applications for two types of grants are welcome: Expanded Projects and Focused Projects. The maximum budgets for proposed projects are $500,000 total costs for Expanded Projects and $250,000 total costs for Focused Projects. All project awards will be for a 24-month duration.
The long-term goal of this opportunity is to investigate the metabolic processes that maintain physiological homeostasis at the sub-cellular and cellular levels, and understand how and when these normal processes go awry. This two-year funding opportunity is explicitly aimed at addressing the mechanisms of metabolism, including its dynamics and resolution, molecular drivers, and the effects of genetic and environmental risk factors on relevant sub-cellular and cellular properties and interactions, and precisely mapping metabolic changes and states across various scales using a broad range of technologies. The projects should aim to use diverse experimental systems beyond immortalized cell lines to ensure the broadest possible insights into cellular and organelle biology. These grants are not intended to support translational research, clinical trials, or drug development.
Examples of potential areas within the scope of this RFA include, but are not limited to:
- Profiling organelles and cells to understand their heterogeneity and metabolic regulation in maintaining homeostasis and how they dynamically evolve to adapt to all types of diverse stressors and metabolic conditions;
- Using metabolic rewiring to study the state and fate of specialized cells (e.g., immune cells, adipocytes, neurons, hepatocytes, etc.) programmed by metabolic processes;
- Using mechanistic studies to understand the function and dysfunction of metabolism at the systems physiology level and provide a framework for understanding the molecular and cellular basis of metabolic diseases;
- Identifying, measuring, and studying molecular level metabolite-protein interactions at scale with high sensitivity and selectivity;
- Developing techniques for metabolic tracing to help identify the origin and fate of metabolites and their contribution to cellular processes and interactions; and
- Establishing metabolomics and/or proteomics methodologies (Mass Spectrometry- and non-Mass Spectrometry-based approaches) to enable high-quality spatial biomolecular analysis of individual organelles and cells.
This opportunity is intended to support active collaborative teams of researchers with access to established resources ready to be extended, scaled, and applied to address key biological questions in the field of metabolism or metabolic physiology in health and disease. The opportunity also aims to support new collaborative teams focused on bridging multiple biology fields to accelerate metabolism research and the development of new tools to measure human biology. Teams may include up to a total of three principal investigators (PIs) with at least one PI with expertise in metabolism, metabolic reprogramming and/or homeostasis, organelle biology, metabolomics tools, or any other related field. All teams within the CZI Single-Cell Biology Network are expected to contribute to the larger community via regular engagement and sharing of learnings, data, samples, and other resources.
Open Science and Collaboration
CZ Science is committed to open and collaborative science to accelerate scientific discovery and support training and development opportunities for next generation researchers (staff scientists, postdoctoral fellows, and graduate students). This is particularly true of early-stage technology development that benefits from rapid and iterative improvements coupled with community feedback to ensure utility. We highly encourage researchers to participate in the development of training materials, courses, etc., and to participate in cross-disciplinary training opportunities across teams.
To accelerate research in the area of metabolism across scales and systems and metabolic physiology in health and disease, CZI seeks investigators who will contribute to a collaborative interdisciplinary network and the advancement of the field.
- Investigators and members of their labs will participate in annual meetings joined by all other funded groups, in smaller meetings focused on specific biological or technical issues, and in monthly webinars.
- Investigators and CZI staff will work together to identify resources and technology that will support the metabolism field as a whole.
- Investigators will commit to the rapid dissemination of all resulting data, protocols, code, reagents, and results prior to publication through resources such as the Human Cell Atlas Data Coordination Platform, Chan Zuckerberg CELL by GENE, protocols.io, GitHub, Addgene, and preprints.