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Research Newsletter - September 2006

Spotlight

This month's Spotlight falls on the new Therapeutic Screening Center at HSCI. The group's leader, Lee Rubin, discusses the highly anticipated lab's direction and expected capabilities.

New Therapeutic Screening Group at HSCI
by Lee Rubin

The new Therapeutic Screening Center at HSCI is being established to take comprehensive advantage of some of the unique aspects of stem cell biology to identify reagents and compounds that either affect cell differentiation or could be therapeutic agents themselves. The lab will be equipped with robotic liquid handling systems, a conventional plate reader for standard measurements such as needed for cell-based luciferase assays, and a high throughput confocal microscope-based detector that will allow non-homogeneous differentiation assays (using, for example, GFP or other fluorescent reporters) to be set up. The group has a special interest in orphan nervous system disorders, but anticipates working with other members of the HSCI community and third parties, including those who have a direct interest in translational research.

We plan to carry out several types of studies: (a) identification of reagents that stimulate cell differentiation along desired lineages; (b) pathway modulation using ES cells as sensitive detectors of many of the major developmentally regulated pathways; (c) directed cell differentiation followed by disease-specific screens and mechanistic studies; (d) discovery of therapeutic agents that act by targeting particular types of stem cells.

We will be conducting several types of screens. For example, cell differentiation can be readily assessed in a "high content" (microscope-based) format by having the desired cell type express GFP under the control of a transcription factor specific to that cell. Screening algorithms are available for quantifying the numbers of GFP+ cells in each well in a rapid way. Molecules that increase the number of GFP+ cells are scored as hits in this type of assay. Another type of assay is constructed around ES cells differentiating, for instance, into a specific type of neuron, such as a motor neuron. Since ES cells can be grown in virtually unlimited numbers it becomes possible to obtain motor neurons in similarly large numbers (billions per week), which allows types of studies not generally possible with non-proliferating cells. One simple screen would be directed at trying to identity molecules or pathways that prevent motor neuron degeneration. The algorithm used for this high content screen is a straightforward count of live cells. Since the ES cells used to generate neurons can be derived from a mouse model of a human disease, this experiment can be further elaborated to become more disease-specific: which pathways or molecules can modulate the survival of motor neurons with an ALS (Lou Gehrig's Disease) or Spinal Muscular Atrophy genotype? Finally, stem cell-directed therapeutics - whether they are molecules that mobilize adult stem cells to promote tissue repair after damage or those that inhibit proliferation of tumor stem cells - can in principle be detected with relatively straightforward high content screens.

All screens need diverse compound libraries to test. We are assembling a large small molecule collection that will, we hope, be comprehensive enough to provide hits in numerous assays and be sufficiently drug-like to facilitate more translational research when that becomes an important goal. We will also be in a position to screen other types of libraries, whether protein or siRNA-based.

Scientific Papers

Review and Commentary

  • Amadio JP, Walsh CA. Brain Evolution and Uniqueness in the Human Genome. Cell. 2006 Sep 22;126(6):1033-1035. Read Abstract.
  • Isacson O. What are the long-term effects of neural grafting in patients with Huntington's disease? Nat Clin Pract Neurol. 2006 Sep;2(9):470-1. Read Abstract.
  • Mullally A, Ritz J. Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation. Blood. 2006 Sep 28. Read Abstract.
  • Rosenzweig A. Cardiac cell therapy--mixed results from mixed cells. N Engl J Med. 2006 Sep 21;355(12):1274-7. Read Abstract.
  • Shivraj Sohur U, Emsley JG, Mitchell BD, Macklis JD. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells. Philos Trans R Soc Lond B Biol Sci. 2006 Sep;361(1473):1477-1497. Read Abstract.
  • Zorn E, Ritz J. Studying Human Regulatory T Cells In vivo. Clin Cancer Res. 2006 Sep 15;12(18):5265-7. Read Abstract.

Blood

  • Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H, Ley TJ, Akashi K, Le Beau MM, Gilliland DG. Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood. 2006 Sep 1;108(5):1708-15. Read Abstract.
  • Clark RA, Kupper TS. IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood. 2006 Sep 12; Read Abstract.
  • Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, Verstovsek S, Dupriez B, Silver RT, Odenike O, Cortes J, Wadleigh M, Solberg LA Jr, Camoriano JK, Gisslinger H, Noel P, Thiele J, Vardiman JW, Hoffman R, Cross NC, Gilliland DG, Kantarjian H; IWG for Myelofibrosis Research and Treatment (IWG-MRT). International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006 Sep 1;108(5):1497-503. Read Abstract.
  • Zada AA, Geletu MH, Pulikkan JA, Muller-Tidow C, Reddy VA, Christopeit M, Hiddemann WD, Behre HM, Tenen DG, Behre G. Proteomic analysis of acute promyelocytic leukemia: PML-RARalpha leads to decreased phosphorylation of OP18 at serine 63. Proteomics. 2006 Sep 25. Read Abstract.

Cancer

  • Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA. Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes. Cancer Res. 2006 Sep 15;66(18):9054-64. Read Abstract.
  • Mowry SE, Ho A, Lotempio MM, Sadeghi A, Blackwell KE, Wang MB. Quality of life in advanced oropharyngeal carcinoma after chemoradiation versus surgery and radiation. Laryngoscope. 2006 Sep;116(9):1589-93. Read Abstract.
  • Newton JR, Kelly KA, Mahmood U, Weissleder R, Deutscher SL. In vivo selection of phage for the optical imaging of PC-3 human prostate carcinoma in mice. Neoplasia. 2006 Sep;8(9):772-80. Read Abstract.

Cardiovascular System

  • Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P, Weissleder R. Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis. Circulation. 2006 Sep 25. Read Abstract.
  • Prunier F, Pfister O, Hadri L, Liang L, Del Monte F, Liao R, Hajjar RJ. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Circ Physiol. 2006 Sep 22. Read Abstract.

Developmental Biology

  • Arango NA, Huang TT, Fujino A, Pieretti-Vanmarcke R, Donahoe PK. Expression analysis and evolutionary conservation of the mouse germ cell-specific D6Mm5e gene. Dev Dyn. 2006 Sep;235(9):2613-9. Read Abstract.
  • Hu G, Tang J, Zhang B, Lin Y, Hanai J, Galloway J, Bedell V, Bahary N, Han Z, Ramchandran R, Thisse B, Thisse C, Zon LI, Sukhatme VP. A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro. J Cell Sci. 2006 Oct 1;119(Pt 19):4117-26. Read Abstract.
  • Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, Depinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16(INK4a). Nature. 2006 Sep 6; Read Abstract.
  • Juriloff DM, Harris MJ, McMahon AP, Carroll TJ, Lidral AC. Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test. Birth Defects Res A Clin Mol Teratol. 2006 Sep 22;76(8):574-579. Read Abstract.
  • Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE. p16(INK4a) induces an age-dependent decline in islet regenerative potential. Nature. 2006 Sep 6; Read Abstract.

Diabetes

  • Evgenov NV, Medarova Z, Pratt J, Pantazopoulos P, Leyting S, Bonner-Weir S, Moore A. In vivo imaging of immune rejection in transplanted pancreatic islets. Diabetes. 2006 Sep;55(9):2419-28. Read Abstract.

Gastrointestinal System

  • Yamamoto-Furusho JK, Barnich N, Xavier R, Hisamatsu T, Podolsky DK. Centaurin Beta 1 down-regulates NOD1 and NOD2-dependent NF-kB activation. J Biol Chem. 2006 Sep 27. Read Abstract.

Imaging

  • Kubo S, Levantini E, Kobayashi S, Kocher O, Halmos B, Tenen DG, Takahashi M. Three-dimensional magnetic resonance microscopy of pulmonary solitary tumors in transgenic mice. Magn Reson Med. 2006 Sep;56(3):698-703. Read Abstract.
  • Lamfers ML, Fulci G, Gianni D, Tang Y, Kurozumi K, Kaur B, Moeniralm S, Saeki Y, Carette JE, Weissleder R, Vandertop WP, van Beusechem VW, Dirven CM, Chiocca EA. Cyclophosphamide Increases Transgene Expression Mediated by an Oncolytic Adenovirus in Glioma-Bearing Mice Monitored by Bioluminescence Imaging. Mol Ther. 2006 Sep 20. Read Abstract.

Immunology

  • Liu L, Fuhlbrigge RC, Karibian K, Tian T, Kupper TS. Dynamic programing of CD8(+) T cell trafficking after live viral immunization. Immunity. 2006 Sep;25(3):511-20. Read Abstract.
  • Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, Leutz A. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006 Oct;7(10):1037-47. Read Abstract.

Nervous System

  • Chang BS, Duzcan F, Kim S, Cinbis M, Aggarwal A, Apse KA, Ozdel O, Atmaca M, Zencir S, Bagci H, Walsh CA. The role of RELN in lissencephaly and neuropsychiatric disease. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 6; Read Abstract.

Technology

  • Hynynen K, McDannold N, Vykhodtseva N, Raymond S, Weissleder R, Jolesz FA, Sheikov N. Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J Neurosurg. 2006 Sep;105(3):445-54. Read Abstract.
  • Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006 Sep 29;313(5795):1929-35. Read Abstract.
  • Yang M, Lim CC, Liao R, Zhang X. A novel microfluidic impedance assay for monitoring endothelin-induced cardiomyocyte hypertrophy. Biosens Bioelectron. 2006 Sep 6; Read Abstract.