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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL100001-04
Application #
8264517
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Program Officer
Thomas, John
Project Start
2009-09-30
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$1,291,950
Indirect Cost
$701,664
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Rowe, R Grant; Wang, Leo D; Coma, Silvia et al. (2016) Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis. J Exp Med 213:1497-512
Rowe, R Grant; Mandelbaum, Joseph; Zon, Leonard I et al. (2016) Engineering Hematopoietic Stem Cells: Lessons from Development. Cell Stem Cell 18:707-20
Kim, Peter Geon; Canver, Matthew C; Rhee, Catherine et al. (2016) Interferon-α signaling promotes embryonic HSC maturation. Blood 128:204-16
Vo, Linda T; Daley, George Q (2015) De novo generation of HSCs from somatic and pluripotent stem cell sources. Blood 125:2641-8
Tamplin, Owen J; Durand, Ellen M; Carr, Logan A et al. (2015) Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell 160:241-52
Anderson, Heidi; Patch, Taylor C; Reddy, Pavankumar N G et al. (2015) Hematopoietic stem cells develop in the absence of endothelial cadherin 5 expression. Blood 126:2811-20
Ablain, Julien; Durand, Ellen M; Yang, Song et al. (2015) A CRISPR/Cas9 vector system for tissue-specific gene disruption in zebrafish. Dev Cell 32:756-64
Jang, Il Ho; Lu, Yi-Fen; Zhao, Long et al. (2015) Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium. Blood 125:1418-26
Schlaeger, Thorsten M; Daheron, Laurence; Brickler, Thomas R et al. (2015) A comparison of non-integrating reprogramming methods. Nat Biotechnol 33:58-63
Kim, Peter Geon; Nakano, Haruko; Das, Partha P et al. (2015) Flow-induced protein kinase A-CREB pathway acts via BMP signaling to promote HSC emergence. J Exp Med 212:633-48

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