Mechanisms of Hematopoiesis in AIDS - The goal of this proposal is to improve the efficiency of stem cell engraftment in stem cell based therapies. It uses a recently defined molecular determinant of hematopoietic stem cell localization to define the specific role of the bone marrow endosteal niche and to develop practical strategies for enhancing stem cell engagement of it. Results from the prior grant period demonstrated that osteoblasts on the endosteal surface were a critical regulator of stem cell function and could be targeted to alter outcomes of stem cell transplantation in vivo. These results have resulted in ongoing clinical trials. Results of the prior grant period also resulted in demonstration that the calcium sensing receptor (CaR) on stem cells specifies the engraftment of stem cells at the endosteal niche in development and transplantation. The current proposal seeks to extend these studies to both understand in greater depth the specific functions of specific stem cell niches in vivo and test pre-clinical models for targeting the stem cell calcium sensing receptor therapeutically. Since drugs targeting CaR are already in clinical use for other indications, the studies proposed here have the potential of rapidly translating to clinical application by re-purposing existing medications.
The specific aims of this proposal are: 1: Exploit the endosteum specifying action of stem cell CaR to define specific functions of the endosteal niche compared with other stem cell niches 2: Modify CaR activity or expression to change stem cell localization and function in settings of clinical importance. These studies are intended to facilitate stem cell therapies through both basic and applied analyses. If successful, they will lead to increased engraftment efficiency of stem cells, a parameter critical for advancing stem cell therapies in blood diseases and cancer, including gene modified stem cells for AIDS. ? ? ?
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 72 publications