This project will provide new understanding of how mesenchymal populations can contribute to the maintenance of a tissue critical for host defense, the hematopoietic system. The proposed aims will inform us about the dynamics of a support population or 'stroma'that is often regarded as a merely supportive architecture for the work of the parenchymal cells that carry out the work of a given organ or tissue. Here will use the tractable system of hematopoiesis to examine the mesenchymal-parenchymal interactions in detail and define whether mesenchymal cells should be considered more broadly in the context of tissue dysfunction and disease. Further, we will learn the molecular basis for at least one variant of a condition of high morbidity, myelodysplasia. Determining whether similar pathways participate in the myelodysplasia of HIV infection may be possible in the out years of the grant, but is considered only feasible if the groundwork detailed here is conducted.

Public Health Relevance

This proposal focuses on defining how the structural components of the bone marrow contribute to the healthy and diseased function of the hematopoietic or blood forming stem cells. It is intended to provide novel opportunities for intervening to overcome defects in blood formation associated with myelodysplasia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-AARR-J (02))
Program Officer
Thomas, John
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Massachusetts General Hospital
United States
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Kalaitzidis, Demetrios; Lee, Dongjun; Efeyan, Alejo et al. (2017) Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. J Clin Invest 127:1405-1413
Palchaudhuri, Rahul; Saez, Borja; Hoggatt, Jonathan et al. (2016) Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-45
Yu, Vionnie W C; Lymperi, Stefania; Oki, Toshihiko et al. (2016) Distinctive Mesenchymal-Parenchymal Cell Pairings Govern B Cell Differentiation in the Bone Marrow. Stem Cell Reports 7:220-35
Lee, Dongjun; Wang, Ying-Hua; Kalaitzidis, Demetrios et al. (2016) Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy. J Clin Invest 126:1300-10
Courties, Gabriel; Herisson, Fanny; Sager, Hendrik B et al. (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 116:407-17
Wang, Weihuan; Yu, Shuiliang; Zimmerman, Grant et al. (2015) Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention. Stem Cells 33:2280-93
Kfoury, Youmna; Scadden, David T (2015) Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 16:239-53
Yu, Vionnie W C; Saez, Borja; Cook, Colleen et al. (2015) Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med 212:759-74
Scadden, David T (2014) Nice neighborhood: emerging concepts of the stem cell niche. Cell 157:41-50
Velardi, Enrico; Tsai, Jennifer J; Holland, Amanda M et al. (2014) Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med 211:2341-9

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