Understanding the Role of Inflammation in Disease

We’ve all had that moment when pollen ignites a sneeze, a virus causes coughing, or a splinter leads to swelling and redness. That’s inflammation, and this natural defense helps our bodies maintain a healthy state and rebound from injury. But chronic inflammation results in harmful diseases such as asthma, arthritis, and heart disease. Inflammation also plays a role in organ failure, neurodegenerative diseases like Alzheimer’s, and many other conditions. Diseases associated with inflammation disproportionately affect underserved communities and vulnerable populations, highlighting the importance of making progress in this area of biology.

A microglia cell in the foreground. It plays an important role in the pathogenesis of Alzheimer’s disease.

Why Study Inflammation?

Knowing more about inflammation at the level of the affected cells and tissues will increase our understanding of many diseases and improve our ability to cure, prevent, or manage them. An intriguing possibility is that multiple diseases involving inflammation are linked by shared cells and pathways that sense and respond to local tissue damage. Yet progress in unraveling the puzzle of local inflammation inside tissues and organs has lagged behind traditional study of the circulating cells of the immune system.

Many questions remain about the role of inflammation in maintaining health and triggering disease. What cells contribute to local immunity in your skin, lungs, or gut? How do these cells interact with other specialized cells in a given tissue? How do they change over time or in response to damage? What are the specific differences in the cells or events associated with acute versus chronic inflammation? What tools and technologies exist — or need to be developed — to help study this complex process in a variety of tissue environments?

Work on inflammation has been distributed among many fields, which has led to fragmented advances that don’t always connect. Important advances in research on the gut, brain, skin, lung, and many other systems all point to a critical role of inflammation in health and disease. While it is a common theme across areas of disease research, inflammation lacks dedicated support as an independent discipline. Instead, funding is often limited to research focused on a single organ or disease. These are important studies, but may be missing opportunities to make connections between key discoveries.

Brain cells.

At the same time, the field of inflammation is being transformed by technology, including single cell mRNA sequencing and various imaging methods that lend spatial and temporal insights. These tools are providing unprecedented information on the identity of all the cells involved and visualizing their physical interactions in a native tissue context. Applying new tools and fostering collaboration across communities of researchers studying different tissues provides a unique opportunity to more efficiently surface commonalities of inflammatory diseases that might ultimately help diagnose, treat, or manage many common conditions.

Listening to the Community

To understand how the Chan Zuckerberg Initiative could have a differentiated impact in addressing challenges in the inflammation field, we spoke with dozens of experts, attended conferences, and hosted a workshop. This workshop brought together experts from medicine, industry, and academia to discuss bottlenecks, the future of the field, and key opportunities. Workshop participants identified three priority areas to move the field forward:

  1. Support for interdisciplinary teams;
  2. Development of tools and technologies that provide insight into the process of inflammation, including analytical methods, and;
  3. Connections to the clinic and improved in vitro models to help pick and validate key disease areas.
CZI Inflammation Workshop meeting participants.

New Inflammation Request for Applications

In response to these needs identified by the field, CZI is launching a new Request for Applications (RFA) centered on single-cell analysis of inflammation. Through these grants, we aim to build a network of interdisciplinary teams that will address shared themes in the cellular basis of inflammation.

CZI will provide support for small teams to carry out two-year pilot projects to study tissue-level inflammatory processes in diverse tissues and disease states. Pilot awards are intended to help new collaborations form, establish technologies and experimental methods, and frame key questions for further investigation.

We seek applications from interdisciplinary teams of two to three research groups with distinct areas of expertise. Team members might include physicians, experimental biologists from different fields, technology developers, or computational scientists. New collaborations are encouraged, as are applications from early-career scientists within six years of their first faculty appointment.

Alzheimer’s disease, showing neurons with amyloid plaques.

Total awards for this grant will be $175,000 in total costs per lab. The application will include a 750-word project summary that details the challenge the team is exploring, the approaches necessary to solve this challenge, and the project’s relevance to inflammation. The application portal is open September 17 to November 19, and full details are available here.

Building on CZI’s Support for Single Cell Biology

CZI’s current work in single cell biology has focused on supporting the Human Cell Atlas, a fundamental reference for cell biology in health and disease. The inflammation RFA begins to take a cellular lens to disease, and looks to the Human Cell Atlas for foundational knowledge to understand cellular mechanisms involved in many diseases. The tools and technologies being used to construct the Human Cell Atlas will help clarify the identity and interactions of cells during inflammation.

Genetics has linked many genes involved in inflammation to common diseases, while single cell biology is rapidly identifying a variety of cells as mediators of normal states and the transition to disease. Studying the resident, migrating, and immune cells involved in inflammation — and the molecular mechanisms that link them — will have far-reaching impact. To that end, this new RFA aims to:

  • Increase knowledge about cells that mediate inflammation across multiple tissues, including what cell types are involved, their molecular properties, and how they or their interaction partners change in various inflammatory conditions; and
  • Develop tools and resources to study specific cell types in inflammatory processes, such as shared tissue resources or new tissue and organoid models.

We also hope this grant program will support community growth and begin to open lines of communication across diverse scientific fields to accelerate advances in inflammation. From our exploration of this field, we are inspired to think broadly about how collaboration and new technologies can be used to bring clarity to a question that touches so many diseases. We look forward to continuing to learn as we support this work.

Jonah Cool, Science Program Officer, Chan Zuckerberg Initiative

Jonah Cool is a cell biologist and geneticist by training, and is currently a Science Program Officer at the Chan Zuckerberg Initiative, where he leads the organization’s efforts to support the international Human Cell Atlas consortium. He was an American Heart Association fellow while completing his PhD at Duke Medical Center, with a focus on the role of vascularization during cell differentiation and organ morphogenesis, and was subsequently a Ruth Kirchstein Fellow at the Salk Institute studying nuclear organization during stem cell differentiation. Dr. Cool previously worked in intellectual property litigation, as well as ran an industry research group working toward therapeutic application of 3D bioprinted human tissue. He has a deep love of cell biology and, in particular, the origins of cellular heterogeneity and how diverse cells assemble into complex tissues.

Chan Zuckerberg Science Initiative

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Supporting the science and technology that will make it possible to cure, prevent, or manage all diseases by the end of the century.

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