IU Indianapolis ScholarWorks :: Browsing by Author "Orschell, Christie M."

Browsing by Author "Orschell, Christie M."

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The Access Technology Program of the Indiana Clinical Translational Sciences Institute (CTSI): A model to facilitate access to cutting-edge technologies across a state
(Cambridge, 2021) Orschell, Christie M.; Skaar, Todd C.; DeFord, Melanie E.; Ybe, Joel; Driscol, Julie; Drury, Christine; Reeves, Lilith; Willis, Monte S.; Reiter, Jill L.; York, Jenna; Orr, Rob; McClintick, Jeanette N.; Sors, Thomas G.; Hunt, Joe; Cornetta, Kenneth; Shekhar, Anantha; Medicine, School of Medicine
Introduction: Access to cutting-edge technologies is essential for investigators to advance translational research. The Indiana Clinical and Translational Sciences Institute (CTSI) spans three major and preeminent universities, four large academic campuses across the state of Indiana, and is mandate to provide best practices to a whole state. Methods: To address the need to facilitate the availability of innovative technologies to its investigators, the Indiana CTSI implemented the Access Technology Program (ATP). The activities of the ATP, or any program of the Indiana CTSI, are challenged to connect technologies and investigators on the multiple Indiana CTSI campuses by the geographical distances between campuses (1–4 hr driving time). Results: Herein, we describe the initiatives developed by the ATP to increase the availability of state-of-the-art technologies to its investigators on all Indiana CTSI campuses, and the methods developed by the ATP to bridge the distance between campuses, technologies, and investigators for the advancement of clinical translational research. Conclusions: The methods and practices described in this publication may inform other approaches to enhance translational research, dissemination, and usage of innovative technologies by translational investigators, especially when distance or multi-campus cultural differences are factors to efficient application.
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.
Alterations to maternal cortical and trabecular bone in multiparous middle-aged mice
(Hylonome, 2017-11) Gu, Alex; Sellamuthu, Rajendran; Himes, Evan; Childress, Paul J.; Pelus, Louis M.; Orschell, Christie M.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
Objectives: During the reproductive cycle, altered calcium homeostasis is observed due to variable demand for mineral requirements. This results in increased bone resorption during the time period leading up to parturition and subsequent lactation. During lactation, women will lose 1-3% of bone mineral density per month, which is comparable to the loss experienced on an annual basis post-menopausal. The purpose of this study was to determine the effect of parity on bone formation in middle-aged mice. Methods: Mice were mated and grouped by number of parity and compared with age matched nulliparous controls. Measurements were taken of femoral trabecular and cortical bone. Calcium, protein and alkaline phosphatase levels were also measured. Results: An increase in trabecular bone mineral density was observed when comparing mice that had undergone parity once to the nulliparous control. An overall decrease in trabecular bone mineral density was observed as parity increased from 1 to 5 pregnancies. No alteration was seen in cortical bone formation. No difference was observed when calcium, protein and alkaline phosphatase levels were assessed. Conclusions: This study demonstrates that number of parity has an impact on trabecular bone formation in middle-aged mice, with substantial changes in bone density seen among the parous groups.
Combined hydration and antibiotics with lisinopril to mitigate acute and delayed high-dose radiation injuries to multiple organs
(Lippincott, Williams & Wilkins, 2016-11) Fish, Brian L.; Gao, Feng; Narayanan, Jayashree; Bergom, Carmen; Jacobs, Elizabeth R.; Cohen, Eric P.; Moulder, John E.; Orschell, Christie M.; Medhora, Meetha; Medicine, School of Medicine
The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study we have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ∼24 mg m-2 day-1 started orally in the drinking water at 7 days after irradiation and continued to ≥150 days) mitigated late effects in the lungs and kidneys after 12.5 Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 days after 13 Gy leg-out PBI. Furthermore lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg-1 day-1 from days 1-14) which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, we mitigated acute and delayed radiation injuries in multiple organs.
Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells
(Elsevier, 2008-05) Orschell, Christie M.; Borneo, Jovencio; Munugalavadla, Veerendra; Ma, Peilin; Sims, Emily; Ramdas, Baskar; Yoder, Mervin C.; Kapur, Reuben; Department of Medicine, IU School of Medicine
OBJECTIVE: Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells. RESULTS: Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1(+)Lin(-) cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK(-/-) cells, although, this increase did not affect the homing potential of more primitive Lin(-)Sca-1(+) SFK(-/-) cells. The stem cell-repopulating defect observed in mice transplanted with SFK(-/-) bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK(-/-) bone marrow cells. CONCLUSIONS: Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells.
Delayed effects of acute radiation exposure (DEARE) in a murine model of the hematopoietic acute radiation syndrome: Multiple-organ injury consequent to total body irradiation
(Office of the Vice Chancellor for Research, 2015-04-17) Quickery, Ariel; Unthank, Joseph L.; Miller, Steven J.; Orschell, Christie M.
Introduction. Victims of radiation exposure from terrorist activity, radiation accidents or radiologic warfare will face a variety of acute and chronic organ injuries requiring multi-faceted approaches to treatment. The hematopoietic system is the most sensitive tissue to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) after exposures of 2-10 Gy in mice. If untreated, H-ARS results in death within weeks from opportunistic infection and/or hemorrhage due to loss of neutrophils and platelets, respectively. However, survivors of ARS are plagued months to years later in life by delayed effects of acute radiation exposure (DEARE), a myriad of chronic illnesses affecting multiple organ systems believed to be due to persistent systemic oxidative stress, inflammation, fibrosis and loss of stem cell self-renewal. Fibrosis and collagen deposition disrupt both normal tissue structure and function and are common to organs with late radiation injury including the kidney and heart after radiation doses >15Gy, but have not been shown to exist after doses as low as those used in the H-ARS model (8Gy). The goal of this study was to determine the extent, if any, of heart and kidney DEARE in survivors of H-ARS. Methods. Mice (male and female C57BL/6) received total body irradiation (TBI; LD50/30 to LD70/30) and kidney and heart were harvested at 9 and 21 months from the H-ARS survivor mice. Tissues were fixed in neutral buffered formalin, paraffin embedded and sectioned, then stained with hematoxylin/eosin (H&E), trichrome, or picosirius red. Serum was collected at 4.3, 9, and 21 months post-TBI and analyzed for blood urea nitrogen (BUN) as an indicator of kidney function. Total RNA was purified from heart and relative changes in NADPH oxidase 2 (Nox2) mRNA expression were assessed by quantitative real-time PCR. Results/Significance. Compared to age-matched non-irradiated controls (NI), renal pathology at 9 months post-TBI was manifest primarily as enlargement of Bowman’s capsule and glomerosclerosis along with limited interstitial fibrosis. By 21 months there was progression of these pathologies as well as extensive interstitial fibrosis, tubular atrophy, cysts, and atubular glomeruli, all of which were more pronounced in TBI mice compared to NI. Consistent with the renal pathology, BUN in TBI mice was significantly increased at 9 and 21 months post-TBI vs. 4.3 months, but normal in NI mice at all time points. In the heart, pericardial, perivascular and interstitial fibrosis were observed at 9 months with increased severity at 21 months post-TBI compared to NI. The perivascular fibrosis was associated with increased medial layer collagen and apparent loss of vascular smooth muscle cells. Nox2 mRNA in heart was increased at 9 and 21 months post-TBI, indicating an increase in oxidant stress. To our knowledge, such striking heart and kidney damage has not been documented after radiation doses as low as those in our H-ARS model (~8Gy) and indicate that DEARE is a concern for individuals exposed to radiation doses previously thought to not elicit late effects.
Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation
(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Unthank, Joseph L.; Miller, Steven J.; Quickery, Ariel K.; Ferguson, Ethan L.; Wang, Meijing; Sampson, Carol H.; Chua, Hui Lin; DiStasi, Matthew R.; Feng, Hailin; Fisher, Alexa; Katz, Barry P.; Plett, P. Artur; Sandusky, George E.; Sellamuthu, Rajendran; Vemula, Sasidhar; Cohen, Eric P.; MacVittie, Thomas J.; Orschell, Christie M.; Department of Surgery, School of Medicine
The threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a Cs radiation source and studied 1-21 mo later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ∼22 to 34 ± 3.8 and 69 ± 6.0 mg dL, p < 0.01 vs. non-irradiated controls) and correlated with glomerosclerosis (29 ± 1.8% vs. 64 ± 9.7% of total glomeruli, p < 0.01 vs. non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peribronchial fibrosis/collagen deposition was observed from ∼9-21 mo post-TBI in kidney, heart, and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in the left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model, which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.
Delayed effects of acute radiation exposure on the cardiovascular system using a murine model of the hematopoietic acute radiation syndrome
(Office of the Vice Chancellor for Research, 2016-04-08) Thungu, Beatrice; Ortiz, Miguel; Unthank, Joseph L.; Orschell, Christie M.; Miller, Steven J.
Introduction. Exposure to high level radiation from accidents or belligerent activities results in acute and chronic organ damage. The hematopoietic system is the most sensitive organ to radiation damage (2-10 Gy) and results in the hematopoietic acute radiation syndrome (H-ARS). Survivors of H-ARS are plagued months to years later with delayed effects of acute radiation exposure (DEARE), characterized by chronic illnesses affecting multiple organ systems. Previous results using the murine H-ARS model showed numerous kidney and heart DEARErelated pathologies similar to humans, including tissue fibrosis and elevated blood urea nitrogen. The goal of this study was to utilize the murine H-ARS model to determine possible roles for abnormal iron metabolism, inflammation, oxidant stress, and senescence in the development of cardiac DEARE. Methods. Mice (C57BL/6; 12 week-old) received total body irradiation (TBI: ~8.5-8.7 Gy, 137Cs, LD50to LD70) and hearts were harvested at various times post-TBI from H-ARS survivors. Paraffin tissue sections were stained with hematoxylin/eosin or Perls Prussian Blue, or reacted with a macrophage-specific antibody (F4/80). Total RNA was purified from fresh tissue and changes in mRNA expression were assessed by real-time PCR for the senescence marker p16 and NADPH oxidase subunits Nox2, Nox4, or p47phox. Results/Significance. Compared to age-matched non-irradiated controls (NI), tissue iron deposits were increased in irradiated (IR) hearts at 4 months, and progressively declined with time post-TBI. Numbers of macrophages were greater in IR vs. NI sections at all time points and decreased with time post-TBI. Nox2 and Nox4 mRNA expression was increased at both 9 and 21 months post-TBI, but p47phox increased only at 21 months. Expression of p16 in IR heart was increased at 7, but not at 22 months post-TBI. Taken together, the results indicate abnormal iron metabolism, inflammation, oxidant stress, and early senescence may contribute to development of cardiac DEARE.
Development of a Model of the Acute and Delayed Effects of High Dose Radiation Exposure in Jackson Diversity Outbred Mice; Comparison to Inbred C57BL/6 Mice
(Wolters Kluwer, 2020-11) Patterson, Andrea M.; Plett, P. Artur; Chua, Hui Lin; Sampson, Carol H.; Fisher, Alexa; Feng, Hailin; Unthank, Joseph L.; Miller, Steve J.; Katz, Barry P.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of Medicine
Development of medical countermeasures against radiation relies on robust animal models for efficacy testing. Mouse models have advantages over larger species due to economics, ease of conducting aging studies, existence of historical databases, and research tools allowing for sophisticated mechanistic studies. However, the radiation dose-response relationship of inbred strains is inherently steep and sensitive to experimental variables, and inbred models have been criticized for lacking genetic diversity. Jackson Diversity Outbred (JDO) mice are the most genetically diverse strain available, developed by the Collaborative Cross Consortium using eight founder strains, and may represent a more accurate model of humans than inbred strains. Herein, models of the Hematopoietic-Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure were developed in JDO mice and compared to inbred C57BL/6. The dose response relationship curve in JDO mice mirrored the more shallow curves of primates and humans, characteristic of genetic diversity. JDO mice were more radioresistant than C57BL/6 and differed in sensitivity to antibiotic countermeasures. The model was validated with pegylated-G-CSF, which provided significantly enhanced 30-d survival and accelerated blood recovery. Long-term JDO survivors exhibited increased recovery of blood cells and functional bone marrow hematopoietic progenitors compared to C57BL/6. While JDO hematopoietic stem cells declined more in number, they maintained a greater degree of quiescence compared to C57BL/6, which is essential for maintaining function. These JDO radiation models offer many of the advantages of small animals with the genetic diversity of large animals, providing an attractive alternative to currently available radiation animal models.
Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer
(American Association for Cancer Research, 2006-03-15) Srirangam, Anjaiah; Mitra, Ranjana; Wang, Mu; Gorski, J. Christopher; Badve, Sunil; Baldridge, Lee Ann; Hamilton, Justin; Kishimoto, Hiromitsu; Hawes, John; Li, Lang; Orschell, Christie M.; Srour, Edward F.; Blum, Janice S.; Donner, David; Sledge, George W.; Nakshatri, Harikrishna; Potter, David A.
Purpose These studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vitro and, if so, how. Experimental Design Ritonavir effects on breast cancer cell growth were studied in the estrogen receptor (ER)-positive lines MCF7 and T47D and in the ER-negative lines MDA-MB-436 and MDA-MB-231. Effects of ritonavir on Rb-regulated and Akt-mediated cell proliferation were studied. Ritonavir was tested for inhibition of a mammary carcinoma xenograft. Results ER-positive estradiol-dependent lines (IC50, 12–24 µmol/L) and ER-negative (IC50, 45 µmol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-α levels notably in ER-positive lines. Ritonavir causes G1 arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D1 but not cyclin E, and depletes phosphorylated Rb and Ser473 Akt. Ritonavir induces apoptosis independent of G1 arrest, inhibiting growth of cells that have passed the G1 checkpoint. Myristoyl-Akt, but not activated K-Ras, rescues ritonavir inhibition. Ritonavir inhibited a MDA-MB-231 xenograft and intratumoral Akt activity at a clinically attainable serum Cmax of 22 ± 8 µmol/L. Because heat shock protein 90 (Hsp90) substrates are depleted by ritonavir, ritonavir effects on Hsp90 were tested. Ritonavir binds Hsp90 (KD, 7.8 µmol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90α short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations. Conclusions Ritonavir inhibits breast cancer growth in part by inhibiting Hsp90 substrates, including Akt. Ritonavir may be of interest for breast cancer therapeutics and its efficacy may be increased by sustained exposure or Hsp90 RNA interference.

Browsing by Author "Orschell, Christie M."

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