Multimodal imaging of myelopoiesis and macrophage accumulation in myocardial infarction

• Applicant: Dr. Lisa Honold
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2017 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 341039326

Following myocardial infarction, infiltrating monocytes and the macrophages they give rise to represent a key factor in infarct healing and tissue remodeling. In patients, high monocyte numbers and prolonged inflammation result in poor prognosis. In agreement, the reduction of infarct macrophages is beneficial in animal models. Although the modulation of immune responses in cardiovascular diseases has become an important research focus, there remains an unmet need of non-invasive macrophage quantification as a success parameter of immune-targeting therapies.The final number of macrophages in steady state and disease is, to a large extent, dependent on the proliferative rate of their progenitors during myelopoiesis, which presents a promising potential intervention point. Proliferation during myelopoiesis is tightly regulated by stage-specific transcription factors promoting cell cycle arrest and differentiation. One is the CCAAT/enhancer-binding protein-alpha (C/EBP-alpha) that is able to reduce proliferation if overexpressed in myeloid progenitors. I propose to apply a multimodal, multiorgan imaging approach to reliably quantify infiltrating macrophages in myocardial infarction and to investigate how modification of stage-specific transcriptional regulation of bone marrow myelopoiesis affects infarct macrophage numbers.In detail, I propose to (i) validate recently developed dextran nanoparticles with ultrasmall diameter and fast kinetics for macrophage quantification by non-invasive whole-body nuclear imaging and (ii) evaluate whether the latter can be used to report on the success of immunomodulatory therapies. In addition, I propose to (iii) apply a genetic approach to lower myeloid progenitor proliferation in the bone marrow by overexpression of C/EBP-alpha and subsequently perform intravital microscopy to investigate the resulting effects on spatial and quantitative dynamics of myeloid differentiation on a single-cell level. The proposed research will provide a non-invasive diagnostic tool to quantify macrophages in myocardial infarction. Additionally, it will answer important open questions about how emergency myelopoiesis in the bone marrow is regulated after myocardial infarction and how fate decisions in myeloid progenitors can be targeted to lower infarct macrophage numbers, thereby improving patient prognosis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Matthias Nahrendorf