OHSU

Research Program

 

  • Vesicle Trafficking of RNA in Acute Myeloid Leukemia

  • Retrovirus Vectors, Cell Entry and Microvesicle Fate

  • Fanconi Anemia, Genetics and Biology

 

Starfish and Anemone, Cape Mears, Oregon

Nanometer sized vesicles that carry nucleic acids and protein are constantly released from cells into the extracellular space. We recently demonstrated that leukemia cells are abundant producers of a class of vesicles called "exosomes" that traffic to bystander cells, where they alter transcription profiles and cell secretion of cytokines and angiogenic growth factors. In this project we are pursuing this observations to understand the regulatory role of AML exosomes during leukemia progression and in the suppression of hematopoietic cells. In addition we are developing biomarker approaches for the detection of minimal residual disease based on exosome miRNA profiles.

The capacity for self-renewal and multipotency render hematopoietic cells also ideal targets to explore the genetic modification as a way of treating genetic and infectious as well as malignant disease. Our lab has long focused on gene transfer using integrating retroviral vectors in the context of gene therapy strategies. Our research using gamma- and HIV-1 derived replication deficient retrovirus vectors has highlighted the critical importance of cell surface receptor expression and vector particle pseudotyping in optimizing gene transfer efficiency. Ongoing studies provide new insight into cell specific, receptor-independent limitations to transduction during particle uptake and reveal the surprising ability of vector particles to enter cellular microvesicle pathways.

Fanconi Anemia (FA), an inherited disorder with prominent bone marrow failure, is a candidate disease for exploring gene transfer technology in hematopoietic stem cells. Working in murine models we have shown that lentiviral vectors are ideally suited for addressing several properties unique to FA stem cells thereby minimizing ex vivo attrition while correcting the cellular phenotype. Work is ongoing to improve our understanding of the role of the microenvironment in FA hematopoietic failure.

Current Projects