Yi Zheng, PhD
Rational design of small molecule inhibitors targeting Rho GTPase activation cascade.
We reported in PNAS and Chemistry & Biology the rational design of a small-molecule inhibitor of the RhoA activator, LARG, that helped stop the spread of laboratory cultured human breast cancer cells, especially when it was used with another chemical inhibitor known as Rhosin/G04 which is specific toward RhoA itself. The studies provide novel therapeutic principle for rational drug design and discovery.
Paul Andreassen, PhD
The Andreassen lab has recently demonstrated that the machinery for homologous recombination is linked to early events in DNA damage signaling by ubiquitin-dependent signaling and PALB2/FANCN. We have also generated novel insight into the function of RAD51 paralogs in DNA repair by finding that RAD51C/FANCO interacts with PALB2/FANCN.
Jose Cancelas, MD, PhD
The Cancelas Lab has been working on the following studies:
- Discovery and elucidation of the role of Vav3 in BCR-ABL lymphoblastic leukemia.
- Identification of connexin43 (Cx43) as a regulator of reactive oxygen content (ROS) in hematopoietic stem cells and description of a novel protective function of bone marrow stroma consisting of scavenging of ROS through Cx43.
- Elucidation of the role of Klf5 in stem cell adhesion and homing to the bone marrow with identification of Rab5 as the crucial downstream gene responsible for loss of integrin mediated cell adhesion in stem cells.
- In vivo demonstration of the safety of platelet additive solution Isoplate to maintain platelet storage for up to five days in a multicenter trial.
- In vivo demonstration of the ability of DMSO to freeze platelets and maintain their viability in a multicenter trial.
Jay Degen, PhD
The Degen Lab is genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18;shown to inhibit perivascular microglial clustering and axonal damage within the central nervous system in a mouse model of multiple sclerosis.
In other work, the Degen Lab has shown thrombin-mediated proteolysis to be an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding cardiovascular disease.
Finally, the Degen Lab has shown the host fibrin(ogen) and the S. aureus-encoded fibrinogen receptor, ClfA, to be dual determinants of bacterial virulence. These findings suggest that therapeutic interventions at the level of fibrinogen could be advantageous in S. aureus septicemia.
Matthew Flick, PhD
The Flick Lab has continued analysis of the pathogenesis of bacterial infection including a publication highlighting the mechanisms of microbe engagement of fibrinogen the pathogenesis of S. aureus septicemia.
In addition, the Flick Lab has initiated a new project, funded by an industry contract with Novo Nordisk, to study the efficacy of recombinant factor XIII in treating inflammatory arthritis.
Hartmut Geiger, PhD
The Geiger Lab published a paper in Nature Medicine on radiomitigation which received national attention.
Elke Grassman, PhD, HCLD
The Grassman Lab qualified four new specialized assays for patient monitoring for a thalassemia gene therapy trial.
The Grassman Lab published two papers in Gene Therapy. One was entitled, "Scale-up and manufacturing of clinical-grade self-inactivating gamma-retroviral vectors by transient transfection." The second paper was entitled, "Critical variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency."
Fukun Guo, PhD
The Guo Lab is studying the following:
- The role of mTOR in hematopoiesis.
- The role of Cdc42 in T cell activation.
- The role of RhoA in T cell development and activation.
- mTOR as a potential therapeutic target in T lymphocytic leukemia.
Carolyn Lutzko, PhD
The Lutzko Lab has developed specialized induced pluripotent stem cells from patients with blood diseases including neutropenia, sickle cell anemia and leukocyte adhesion deficiency. These specialized stem cells allow us to produce blood cells with the "disease" in the dish to directly develop and test gene, cell and drug therapies for these blood diseases.
Punam Malik, MD
The Malik Lab is working on:
- A clinical trial for gene therapy for sickle cell disease.
- Gene therapy for HLH with Drs. Jordan and Risma.
- A clinical trial for sickle nephropathy.
Ruhikanta Meetei, PhD
The Meetei Lab has:
- Discovered a 20kDa subunit of FA core complex protein and it was published in the journal Blood.
- Identified an important site of phosphorylation (S1045) in FANCM protein in response to DNA damage. This was published in the Cancer Research journal.
James Mulloy, PhD
The Mulloy Lab has:
- Defined the role that Thrombopoeitic/MPL/Bcl-xL plays downstream of the AML1-ETO oncogene.
- Established a chemotherapy regimen for AML in immunodeficient mice.
Nicolas Nassar, PHD
The Nassar Lab is working on the following:
- Rational design of a Vav/Rac inhibitor as a new therapy for high risk B-ALL.
- A novel and rationally designed Ras inhibitors for high risk B-ALL Multi-target therapy.
Dao Pan, PhD
The Pan Lab has reported in PNAS the development of a recombinant receptor-binding domain (Rb) of ApoE that enables protein delivery across the blood-brain barrier in mice when being tagged with a lysosomal enzyme as a fusion protein. The studies provide a noninvasive and BBB-targeted procedure for delivery of large molecule therapeutic agents to treat diseases involving the brain.
The Pan lab has also conducted preclinical evaluation of the blood-brain-barrier targeted Rb they recently developed, and showed that long-term systemic delivery of BBB-targeted IDUA-Rb could achieve superb neurological benefits over control protein with complete normalization of behavioral deficits in high-dosage groups and partial correction of brain pathology in medium group. This study has been presented at the 16th Annual meeting of American Society of Cell and Gene Therapy, and Dr. Salim El-Amouri from the lab received a 2013 ASGCT Travel Award.
The Pan lab has recently demonstrated for the first time that megakaryocytes/platelets are capable of over-producing, packaging and storing a lysosomal enzyme which retains proper catalytic activity, lysosomal enzyme trafficking and endogenous M6PR-mediated uptake, as well as the ability of cross-correction in patient’s cells. This study has been presented at the 2012 ASH meeting in December, and Dr. Mei Dai from the lab received ASH Abstract Achievement Award.
The Pan lab has recently demonstrated that long-term visceral phenotypic corrections could be further improved by stress erythropoiesis with complete normalization in spleen of MPS I mice with minimum HSC gene transfer (<1%) after lentiviral vector-mediated hematopoietic stem cell gene therapy using a erythroid/megakaryocytic promoter. These studies provide valuable preclinical information that may lead to future clinical trial. This study has been presented at the 16th Annual meeting of American Society of Cell and Gene Therapy, and Dr. Jing-fen Han, from the lab, has received a 2013 ASGCT Travel Award.
Qishen Pang, PhD
The study, “Link between abnormal HSC differentiation and disease progression in FA”, shows that FA deficiency enhances Notch signaling in multipotential progenitors (MPPs), which is correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. The findings have implications for understanding the pathogenesis of BM failure and leukemia in FA, and suggest possible translational approaches to these devastating clinical complications. A manuscript describing these studies is in press in J. Immunology.
In addition, the study, “Targeting the FA pathway in sensitizing leukemia to chemotherapy”, demonstrates that the mTOR kinase inhibitor pp242 enhances anti-tumor activity of conventional chemo-drugs in vitro and in vivo by suppressing FANCD2 and consequently augmenting DNA damage leading to apoptosis. The finding suggests that inhibition of the FA pathway coupled with chemo-therapy may be beneficial for cancer treatment. A manuscript describing these studies is in press in Leukemia.
Nancy Ratner, PhD
The Ratner Lab has published a paper in the Journal of Neuroscience showing that Rac1 controls Schwann cell myelination through cAMP and NF2/merlin. A critical role for cAMP downstream of the small GTPase Rac1 had not previously been defined in vivo.
The Ratner Lab published a paper showing Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition Acta Neuropathol. This shows for the first time that macrophages comprise 30% of cells in neurofibromas.
The Ratner Lab published a paper in The Journal of Clinical Investigation that shows MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. This paper shows that MEK inhibition shrinks most neurofibromas in an accurate mouse model of NF1 disease. The paper received considerable PR and two ongoing clinical trials have resulted from this work.
The Ratner Lab published a paper in Cancer Research that shows nPTEN and NF1 inactivation in Schwann cells produce a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors.
The Ratner Lab published a paper in Sarcoma showing then conditional Inactivation of Pten with EGFR Overexpression in Schwann Cells Models Sporadic MPNST.
The Ratner Lab published a paper in Nature Genetics showing the forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. This is an important paper identifying novel potential driver mutations in MPNST, an incurable human sarcoma.
The Ratner Lab published a paper in Cancer Discover showing the Canonical Wnt/beta-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance. This is a paper identifying multiple modes for activating b-catenin signaling MPNST, an incurable human sarcoma.
The Ratner Lab published a paper in Oncogen showing EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.
Damien Reynaud, PhD
The Reynaud laboratory was set up in March 2013 with the purchase of essential equipment. Recruitment and training of lab personnel (one research assistant and one postdoctoral fellow) has been initiated. The first set of experiments describing the hematopoietic compartments present in the neonate bone marrow have been performed.
Daniel Starczynowski, PhD
The Starczynowski Lab was awarded a Gabrielle’s Angels Foundation Research Award.
The Starczynowski Lab published “Cytotoxic effects of Bortezomib in MDS/AML depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1” in Blood (July 2012).
Johannes van der Loo, BA, MS, PhD
The van der Loo Lab published a paper describing the development and scale-up for manufacturing of clinical-grade gamma-retroviral vectors in a bioreactor. The paper was published in the journal Gene Therapy.
The van der Loo Lab published a paper on the critical variables evaluated during the clinical-grade production of a self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency in an international multi-institutional phase I trial. The product is currently being used in London, Paris, Los Angeles, Boston and Cincinnati. The paper was published in the journal Gene Therapy.
The van der Loo Lab completed clinical manufacturing of three (3) lots of GMP-grade lentiviral vector for the treatment of Sickle Cell Anemia for a phase I trial to be opened at Cincinnati Children’s (PI: Malik).
Ronald Waclaw, PhD
The Waclaw Lab is analyzing the role of the RASopathy gene, Shp2 (PTPN11) during mouse brain development. We have found that loss of Shp2 and misexpression of a Noonan Syndrome GOF mutation impacts the normal generation and differentiation of oligodendrocytes in the telencephalon. We are currently writing this manuscript for submission.
The Waclaw Lab is analyzing the role of the RASopathy gene, NF1 (neurofibromin) during mouse basal ganglia development. We have found that loss of NF1 impacts both the striatal differentiation and normal formation of striatal circuitry. We are currently writing a manuscript for submission.
Additionally, the Waclaw Lab is analyzing mouse models of glioma at "pre tumor" stages to determine the role of early developmental genes at early stages of gliomagenesis. We have identified several candidate genes normally expressed in progenitor niches of the telencephalon and are now characterizing several defined signaling pathways in combination with these factors.
Jianqiang Wu, MD, MS
The Wu Lab is studying the following:
Stat3 in neurofibroma initiation and maintenance.
miR-155 and RUNX function in neurofibroma formation and therapy.