Investigating Histone Acetylation Modulator Function in Alveolar Regeneration and Disease Pathogenesis

Influenza and COVID-19 remain significant global health concerns, with viral infections in the lungs often leading to alveolar damage and, in severe cases, progressing to acute respiratory distress syndrome (ARDS). ARDS development is closely linked to impaired alveolar regeneration, which relies on the proliferation and differentiation of alveolar type 2 (AT2) stem cells into alveolar type 1 (AT1) cells to restore lung function. The precise molecular mechanisms that govern alveolar regeneration remain poorly understood. Here I have established a high-throughput in vivo genetic screening system in mice to systematically search for essential epigenetic modulators that contribute to alveolar regeneration. Preliminary results have identified numerous histone acetylation pathway related genes, including lysine acetyltransferase 8 (Kat8), are required for AT2 restoration and may contribute to differentiation towards AT1 cells. Kat8 has not previously been linked to alveolar regeneration, however, a key component of its associated protein complex and downstream target genes has been identified in genome-wide association studies as risk genes for idiopathic pulmonary fibrosis, a deadly disease also caused by impaired alveolar regeneration. This proposal aims to clarify the mechanisms by which Kat8 regulates alveolar regeneration, determine the association of Kat8 loss of function with pulmonary fibrosis and further enhance the existing in vivo screen system by integration with single cell techniques to comprehensively map other histone acetylation modulation functions. This study will shed light on epigenetic mechanisms underlying AT2-mediated alveolar regeneration and disease pathology, with the potential to inform the design of novel therapeutic approaches targeting histone acetylation modulators to promote alveolar regeneration and combat fibrosis progression. The proposed research plan will be executed at the Broad Institute of MIT and Harvard, Cambridge, under the mentorship of Dr. Fei Chen and Dr. Jayaraj Rajagopal, with overall complementary expertise in the field of genomics, synthetic biology, and lung stem cell biology. My career objective is to become a tenure-track faculty pioneering and simultaneously training next-generation scientists at the intersection of technology and lung stem cell biology. To accomplish my career goals, I have put together a comprehensive training plan to enhance the overall skill sets required to establish myself as a successful independent investigator. To ensure timely progress toward fulfilling my rigorous research plan and career goals, I have gathered an expert advisory committee comprising Dr. Carla Kim, Dr. Darrell Kotton, Dr. Jason Buenrostro, and Dr. Ruth Franklin, with whom I will regularly discuss my research progress and receive invaluable career development guidance, the key ingredient to my pathway to scientific independence. Project Number: 1K99HL181185-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Dawei Sun | Institution: BROAD INSTITUTE, INC., CAMBRIDGE, MA | Award Amount: $130,593 | Activity Code: K99 | Study Section: NHLBI Mentored Transition to Independence Study Section[MTI (MA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL18118501