Our groups have common interests in the development of improved techniques for generating pluripotent stem cells, directing their differentiation into relevant tissues, and in disease modeling in two major systems of central interest to the NHLBI-the cardiovascular system and the blood. While the causative genetic lesion has been identified for many conditions, certain inborn and acquired hematologic disorders continue to cause significant morbidity and mortality. The limitations of animal and in vitro models is particularly relevant to the hematopoietic system, where engineering gene defects into mouse strains has failed to phenocopy cardinal features of diseases like Fanconi anemia and Down Syndrome. Human models would offer a relevant system to study these diseases and to develop therapeutics. We have pioneered methods for somatic cell reprogramming to generate mouse and human induced pluripotent stem cells (IPS) and bring considerable experience to the directed differentiation of embryonic stem (ES)/ IPS cells into hematopoietic lineages. We wish to exploit these new humanized research tools to complement our traditional expertise in zebrafish and murine models to study hematopoietic development and disease pathophysiology. In this proposal we plan to create and study human IPS cells for genetic blood diseases that: disrupt genomic stability (Fanconi's anemia and Dyskeratosis congenita), specify aberrant nucleolar or ribosomal proteins (Shwachman-Bodian-Diamond Syndrome and Diamond-Blackfan Anemia), and represent a constitutional' trisomy with prominent hematologic and cardiac anomalies (Down Syndrome). With these IPS cells, we will explore disease phenotypes, pursue strategies for gene repair, and search for novel therapeutics that might ameliorate these conditions. This proposal is part of a collaborative R03 application with Drs Ken Chien and Kit Parker, cardiovascular researchers at the Massachusetts General Hospital, and Doug Melton, a stem cell researcher at Harvard University, and has three specific aims:
Aim #1 : Generate human induced pluripotent stem cells from patients with genetic and acquired disorders of the hematopoietic system.
Aim #2 : Explore the hematopoietic phenotypes of disease-specific IPS cells.
Aim #3 : Investigate methods for gene repair, and pursue chemical and genetic screening to identify novel small molecules and genetic pathways to ameliorate the disease phenotypes in vitro.
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| Lahvic, Jamie L; Ammerman, Michelle; Li, Pulin et al. (2018) Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132. Proc Natl Acad Sci U S A 115:9252-9257 |
| MacLean, Glenn A; McEldoon, Jennifer; Huang, Jialiang et al. (2018) Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells. Sci Rep 8:8001 |
| Lummertz da Rocha, Edroaldo; Rowe, R Grant; Lundin, Vanessa et al. (2018) Reconstruction of complex single-cell trajectories using CellRouter. Nat Commun 9:892 |
| Mandelbaum, Joseph; Shestopalov, Ilya A; Henderson, Rachel E et al. (2018) Zebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma. J Exp Med 215:2673-2685 |
| Kapp, Friedrich G; Perlin, Julie R; Hagedorn, Elliott J et al. (2018) Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature 558:445-448 |
| Cesana, Marcella; Guo, Michael H; Cacchiarelli, Davide et al. (2018) A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development. Cell Stem Cell 22:575-588.e7 |
| Sugimura, Ryohichi; Jha, Deepak Kumar; Han, Areum et al. (2017) Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545:432-438 |
| Wiley, D S; Redfield, S E; Zon, L I (2017) Chemical screening in zebrafish for novel biological and therapeutic discovery. Methods Cell Biol 138:651-679 |
| Doulatov, Sergei; Vo, Linda T; Macari, Elizabeth R et al. (2017) Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci Transl Med 9: |
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