Dissecting the Pleiotropic Roles of NFkB in Hematopoietic Aging

About This Grant

PROJECT SUMMARY / ABSTRACT Hematopoietic aging is characterized by chronic inflammation, hematopoietic stem cell (HSC) dysfunction, and hematopoietic bias toward myeloid lineages, leading to less efficient immune responses and increasing incidence of hematologic neoplasia. Emerging evidence from our group and others shows that NFκB-mediated chronic inflammatory responses affect HSCs and their cellular niches in different ways. Elevated NFκB activity within HSCs leads to loss of replicative capacity, while in contrast, elevated NFκB within the bone marrow niche drives epigenomic reprogramming of HSCs and myeloid bias of their progeny. These observations lead to the central hypothesis of this proposal, that unique NFκB responses in HSCs and their niches together form a biologic buffering mechanism balancing inflammatory hematopoietic responses with HSC preservation to maintain lifelong blood production. Importantly, chronic and dysregulated inflammation is implicated in a wide range of blood disorders, yet the mechanisms governing HSC and niche cell responses remain unclear. Thus, the proposed studies are expected to open avenues of inquiry with broad relevance to hematopoietic aging, clonal hematopoiesis, myeloid neoplasia, aplastic anemia, iatrogenic myelosuppression, and more. This mentored career development award will support the advanced research training of Dr. Jennifer Chia, a hematopathologist at UCLA, to become an independent academic physician-scientist in the field of hematopoiesis. Dr. Chia received her MD and PhD degrees from the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD program, and completed her Anatomic Pathology residency and Hematopathology fellowship at UCLA. She is now pursuing post-doctoral research training in the laboratory of Dr. Alexander Hoffmann, an internationally recognized expert in NFκB and the signaling systems that control immune cell function and fate decisions. The specific training objectives detailed in this proposal are to develop expertise in 1) inflammatory signaling and animal models of immune dysregulation; 2) HSC biology; 3) bioinformatics; and 4) the bone marrow niche. Training will be provided through mentorship by senior faculty members who are leaders in their fields, coursework, seminars, and conferences, all in the context of UCLA’s extensive resources and strong institutional commitment to the development of physician-scientists.