Investigating Mechanisms Controlling the Development of Tim4+ Macrophages

1. Overview of research in the laboratory There are currently two focuses of my lab: One focus is on mechanisms controlling the development of macrophages after differentiating from monocytes in the steady state and disease settings. This is an important but poorly understood biological process. Most studies in the past have been focusing on the differentiation process from monocytes to macrophages, not much on their continued development afterwards. As described in the application, we propose a novel concept that in order to develop into professional phagocytes that handle apoptotic cells efficiently and “silently”, the Tim4- macrophages need to be “trained and tested” continuously to become qualified to develop into Tim4+ macrophages. Furthermore, we aim to reveal novel epigenetic and metabolic regulators for this developmental process. The other focus of my lab is to leverage myeloid cell activation to treat metastatic ovarian cancer. The first manuscript of my lab on this topic was recently published in the Journal of Experimental Medicine and has received top 2-3% attention scores. 2. Goals for the next five years The goals include the following: (1) to test how efferocytosis and IL4 signaling synergistically promote the development of Tim4+ macrophages, (2) to profile the epigenetic and metabolic changes of macrophages during their development into Tim4+ macrophages, and (3) to identify novel epigenetic and metabolic regulators for the development of Tim4+ macrophages. 3. Overall vision of the research program This research program is designed to address the fundamental question: “What factors dictate the development Tim4+ macrophages from Tim4- macrophages after they finish differentiation from monocytes?”. This question is of paramount significance for general medicine because of the broad presence and key role of Tim4+ macrophages in virtually all tissues as well as them being the best efferocytes, i.e., phagocytosing apoptotic cells silently and efficiently, in the body. Dysregulation of Tim4+ macrophages could affect a wide spectrum of diseases, from autoimmune diseases to severe infections, to cancer, and to tissue injury. Based on published results from others and promising data fully generated in my own laboratory at The Wistar Institute in the past year, we propose a new model for the development of Tim4+ macrophages: “continuous “training and testing” of silent and efficient efferocytosis by macrophages eventually produces Tim4+ macrophages”. Completion of this research program will provide convincing evidence for this new model and reveal novel epigenetic and metabolic regulators for this process. This will open a new direction for modulating macrophage heterogeneity. Considering its significance in almost all diseases, future work will focus on manipulating the newly identified regulators to modulate macrophage subsets for better disease outcomes. Project Number: 1R35GM162440-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Nan Zhang | Institution: WISTAR INSTITUTE, PHILADELPHIA, PA | Award Amount: $506,550 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269470