Christie Orschell

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https://hdl.handle.net/1805/14111

Side effects of cancer chemotherapy and radiotherapy include destruction of bone marrow stem and progenitor cells. These cells help the body fight against life-threatening infection and hemorrhage. Exposure from radiological terrorism or accidents also leads to severe bone marrow damage. There are many FDA-approved medications to help bone marrow recovery after cancer treatment, but currently only two approved medical countermeasures (MCM) for individuals exposed to lethal doses of radiation. These medications, Neupogen and Neulasta, are “repurposed” from the cancer field.

Dr. Christie Orschell’s laboratory developed mouse models of the Hematopoietic-Acute Radiation Syndrome (H-ARS) and the Delayed Effects of Acute Radiation Exposure (DEARE) for efficacy testing of MCM against radiation according to the FDA Animal Rule. Under the Animal Rule, which guides drug development when human efficacy studies are unethical or unfeasible, development of radiation MCMs must first use animal models. Her models contributed to the approval of Neupogen and Neulasta, and have been promoted by the NIH to undergo qualification as a “drug development tool” by the FDA, which would allow the model to be publicly available for use in drug development programs and included in FDA submissions without the need to reconfirm suitability of the model.

Dr. Orschell’s work to develop animal models for radiation drug discovery is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.

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Browsing Christie Orschell by Author "Alvarez, Marta"

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    Aging negatively impacts the ability of megakaryocytes to stimulate osteoblast proliferation and bone mass
    (Elsevier, 2019) Maupin, Kevin A.; Himes, Evan R.; Plett, Artur P.; Chua, Hui Lin; Singh, Pratibha; Ghosh, Joydeep; Mohamad, Safa F.; Abeysekera, Irushi; Fisher, Alexa; Sampson, Carol; Hong, Jung-Min; Childress, Paul; Alvarez, Marta; Srour, Edward F.; Bruzzaniti, Angela; Pelus, Louis M.; Orschell, Christie M.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Osteoblast number and activity decreases with aging, contributing to the age-associated decline of bone mass, but the mechanisms underlying changes in osteoblast activity are not well understood. Here, we show that the age-associated bone loss critically depends on impairment of the ability of megakaryocytes (MKs) to support osteoblast proliferation. Co-culture of osteoblast precursors with young MKs is known to increase osteoblast proliferation and bone formation. However, co-culture of osteoblast precursors with aged MKs resulted in significantly fewer osteoblasts compared to co-culture with young MKs, and this was associated with the downregulation of transforming growth factor beta. In addition, the ability of MKs to increase bone mass was attenuated during aging as transplantation of GATA1low/low hematopoietic donor cells (which have elevated MKs/MK precursors) from young mice resulted in an increase in bone mass of recipient mice compared to transplantation of young wild-type donor cells, whereas transplantation of GATA1low/low donor cells from old mice failed to enhance bone mass in recipient mice compared to transplantation of old wild-type donor cells. These findings suggest that the preservation or restoration of the MK-mediated induction of osteoblast proliferation during aging may hold the potential to prevent age-associated bone loss and resulting fractures.