Understanding the Role of Inflammation in Disease – Chan Zuckerberg Science Initiative

New RFA Supports Interdisciplinary Teams Studying Basic Tissue Biology and Developing Tools

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 usually helps our bodies maintain a normal state and rebound from harm. But inflammation isn’t always beneficial — it results in harmful chronic diseases such as asthma, arthritis, and heart disease. Inflammation is also associated with other large classes of disease, including obesity and neurodegenerative diseases like Alzheimer’s.

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

Why Inflammation?

Knowing more about inflammation at the level of the affected cells and tissues will greatly improve our understanding of the causes of many diseases and our ability to cure, prevent, or manage them. An intriguing possibility is that multiple diseases involving inflammation are not discrete, but rather linked by shared cells and pathways that sense and respond to local damage. Yet progress in unraveling the puzzle of inflammation has lagged behind traditional study of the immune system, which typically focuses on cells circulating in your bloodstream, not the resident cells that interact locally inside tissues and organs.

We know too little about the role of inflammation in maintaining health and triggering disease. There are many questions we still have to answer. 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?

Pioneering work has begun to highlight the critical role of inflammation during a wide array of biological events. These studies have also started to reveal that continued innovation requires diverse teams — it is not typical that a neuroscientist who describes inflammation as a hallmark of a neurodegenerative disorder will be able to navigate both the complexity of the nervous system and the immune system.

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 connect key advances.

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 and help diagnose, treat, or manage many common indications.

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

Following extensive community engagement, CZI is launching a new Request for Applications (RFA) centered on inflammation. Through these grants, we aim to build a network of interdisciplinary teams focused on diverse questions related to inflammation.

CZI will provide support for small teams to carry out two-year pilot projects in under-explored areas or questions that seek to foster connections within the inflammation community. Pilots might support the application of new technologies or approaches and leverage the complementary skills of the team to advance understanding of tissue-level inflammatory processes in diverse tissues and disease states. Pilot awards are intended to help new collaborations form and begin to explore difficult questions. CZI will also look to this group and the community at large to help surface key opportunities and challenges that would benefit from future support or improved technology.

We will accept applications from teams of two to three researchers with distinct expertise. New collaborations are encouraged, and priority will be placed on interdisciplinary and diverse teams. For example, a potential collaboration could include a physician, a clinical research coordinator, and a tissue expert, with a project goal of generating and interpreting high-quality tissue resources and metadata. Another example could be biologists and a tissue engineer teaming up to test next-generation in vitro models that accurately model human biology. Teams could focus on uniting technology developers with tissue experts, or even groups of various tissue experts looking to explore common themes in diverse organs.

In all cases, teams will be encouraged to include early career scientists and also clarify how their team and project will promote diversity, equity and inclusion in terms of the inflammatory conditions being studied and the composition of the research network. Diseases associated with inflammation disproportionately affect underserved groups in all countries, and we hope this work will provide an opportunity to make progress toward treatment or diagnostics for many of them.

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 writing a 750-word project summary that details the challenge the team is exploring, the diverse skill sets necessary to solve this challenge, and the project’s relevance to inflammation. Application details will be available on September 17, and the application portal will open the same day.

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 and whole organ analysis 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 cellular interactions that mediate inflammation in multiple tissues, including what cell types are involved and how they or their interaction partners change in various inflammatory conditions; and
  • Implicate specific cell types in complex disease processes, or as off-target drivers of complications associated with disease or treatment.

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 are grateful to the community for their guidance and look forward to continuing to learn and evolve our support.

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.

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