Deciphering regulatory mechanism of trained immunity in aged HSCs and clonal hematopoiesis of indeterminate potential (CHIP)
| Project/Area Number |
22K16302
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kobe University |
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Principal Investigator |
Afroj Tania 神戸大学, 医学研究科, 学術研究員 (50913034)
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| Project Period (FY) |
2022-04-01 – 2024-03-31
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| Project Status |
Granted (Fiscal Year 2022)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Hematopoietic stem cell / Humanized mice / Trained immunity / Aging / CHIP / Clonal hematopoiesis / Xenograft model |
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| Outline of Research at the Start |
Hematopoiesis is considered as a life-long production house of immune cells and the integral component of trained immunity.
Notably, aging is coupled with functional derangements in immune cells and clonal hematopoiesis. The regulation of trained immunity in aging and clonal hematopoiesis (CHIP) is currently unknown. Here, I propose to uncover the regulatory mechanism of aging and CHIP pathogenesis by trained immunity, using humanized mouse models that are given several hematopoietic stress related to aging, hope to open a new dimension of “healthy aging”.
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| Outline of Annual Research Achievements |
In the original research proposal, the objective was to investigate the functional impact of induced trained immunity in aged hematopoietic stem cells (HSCs) and its role in the pathogenesis of clonal hematopoiesis of indeterminate potential (CHIP).
During FY2022, the focus was on establishing a humanized mouse model by transplanting human cord blood-derived HSCs. The initial step involved establishing a connection with a cord blood bank to acquire fresh samples of human cord blood. A protocol was then developed to obtain high-quality CD34+ HSCs through cell sorting. Additionally, several immunodeficient mouse models were carefully selected to assess their compatibility for human HSC transplantation and evaluate the survival rates of humanized mice. The survival of humanized mice with aging depends on selective mouse strains and HSCs engraftment. Following the transplantation of HSCs (CD34+) into the humanized mice, the differentiation of these cells into mature immune cells has been clearly characterized and delineated.
To achieve the research goals, investigations are underway to identify genetic mutations in the target genes of the sorted human cord blood HSCs (CD34+ cells).
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
Due to unforeseen circumstances, I made the decision to transfer my academic pursuits to Kobe university from Kyoto University. While I anticipated a seamless transition, there were several factors that contributed to the delay in my research progress including administrative procedure, adjusting new environment etc. Familiarizing myself with the new research facilities, building new relationships with faculty members and peers, and settling into a different academic culture took some time, which further impacted the progress of my research.
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| Strategy for Future Research Activity |
To further explore the implications of my project, I will introduce stress to the hematopoietic stem cell (HSC) compartment using various stimuli such as a fungal cell wall component, LPS (lipopolysaccharide), tumors, or drugs.
Subsequently, I will evaluate the effects of the immune response by investigating changes in the HSCs themselves. This analysis will involve examining alterations in cytokine production, evaluating modifications in myeloid effector functions such as phagocytosis and cytotoxic effects. These assessments will provide insights into how the trained immune response impacts HSC behavior.
Additionally, I plan to investigate the gene expression profile of HSCs using RNA-seq analysis. This approach will help unravel the underlying molecular mechanisms and pathways associated with the trained immune response in HSCs, specifically in the context of aging and blood malignancies.
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Report
(1 results)
Research Products
(3 results)
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[Journal Article] Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade2023
Author(s)
Mitsuhashi Atsushi, Koyama Kazuya, Ogino Hirokazu, Afroj Tania, Nguyen Na Thi, Yoneda Hiroto, Otsuka Kenji, Sugimoto Masamichi, Kondoh Osamu, Nokihara Hiroshi, Hanibuchi Masaki, Takizawa Hiromitsu, Shinohara Tsutomu, Nishioka Yasuhiko
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Journal Title
Cell Reports
Volume: 42
Issue: 3
Pages: 112162-112162
DOI
Related Report
Peer Reviewed / Open Access
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