The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Richard A Flavell - One of the best experts on this subject based on the ideXlab platform.

  • transgenic expression of human signal regulatory protein alpha in rag2 γc mice improves engraftment of human hematopoietic cells in humanized mice
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Till Strowig, Anthony Rongvaux, Chozhavendan Rathinam, Hitoshi Takizawa, Chiara Borsotti, William M Philbrick, Elizabeth E Eynon, Markus G Manz, Richard A Flavell
    Abstract:

    Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γc−/− (NSG) and BALB/c Rag2−/−γc−/− mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2−/−γc−/− mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2−/−γc−/− mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated.

  • transgenic expression of human signal regulatory protein alpha in rag2 gamma c mice improves engraftment of human hematopoietic cells in humanized mice
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Till Strowig, Anthony Rongvaux, Chozhavendan Rathinam, Hitoshi Takizawa, Chiara Borsotti, William M Philbrick, Elizabeth E Eynon, Markus G Manz, Richard A Flavell
    Abstract:

    Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γ(c)(-/-) (NSG) and BALB/c Rag2(-/-)γ(c)(-/-) mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2(-/-)γ(c)(-/-) mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2(-/-)γ(c)(-/-) mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated.

Ryan L Hoiland - One of the best experts on this subject based on the ideXlab platform.

  • influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m
    The Journal of Physiology, 2021
    Co-Authors: Christopher K Willie, Ryan L Hoiland, Alexander Patrician, Alexandra M Williams, Christopher Gasho, Prajan Subedi, James D Anholm, Aimee L Drane, Michael M Tymko
    Abstract:

    Key points Iron acts as a cofactor in the stabilization of the hypoxic-inducible factor family, and likely plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either 1) ascent to high altitude, or 2) following partial acclimatization, when compared to high-altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders, compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature. Abstract To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the hematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: 1) a nine-day ascent to 5050m (20 lowlanders; 12 Sherpa), and 2) following partial acclimatization (11±4 days) to 5050m (18 lowlanders; 20 Sherpa), where both groups received either an i.v. infusion of iron (iron (iii)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050m (p = 0.016 and p = 0.029 respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (p = 0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxemia (PI O2 = 67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude. This article is protected by copyright. All rights reserved.

  • ubc nepal expedition phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude
    The Journal of Physiology, 2019
    Co-Authors: Ryan L Hoiland, Mike Stembridge, Connor A Howe, Howard H Carter, Joshua C Tremblay, Chris K Willie, Joseph Donnelly, David B Macleod, Chris Gasho, Lindsey M Boulet
    Abstract:

    KEY POINTS: Sherpa have lived in the Nepal Himalaya for 25-40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives. We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH. The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema. ABSTRACT: Debilitating side effects of hypoxia manifest within the central nervous system; however, high-altitude natives of the Tibetan plateau, the Sherpa, experience negligible cerebral effects compared to lowland natives at extreme altitude. Phenotypical optimization of the oxygen cascade has been demonstrated in the systemic circulation of Tibetans and Sherpa, likely underscoring their adapted capacity to thrive at altitude. Yet, little is known as to how the cerebral circulation of Sherpa may be adapted. To examine potential differences in cerebral oxygen delivery in Sherpa compared to lowlanders we measured arterial blood gases and global cerebral blood flow (duplex ultrasound) during a 9 day ascent to 5050 m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400 m (-30.3 ± 21.6%; P < 0.01) and 4371 m (-14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modelling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximately 100 mL min-1 (∼17-34%) lower cerebral blood flow in Sherpa compared to lowlanders across ascent to altitude (P = 0.046). To ascertain the role of chronic hypoxia independent of the ascent, Sherpa who had not recently descended were also examined at 5050 m. In these Sherpa, cerebral oxygen delivery was also lower compared to lowlanders (∼22% lower; P < 0.01). We highlight new information about the influence of race and genetic adaptation in the regulation of cerebral oxygen delivery. The lower cerebral oxygen delivery in the Sherpa potentially represents a positive adaptation considering Sherpa endure less deleterious cerebral consequences than lowlanders at altitude.

  • chemoreceptor responsiveness at sea level does not predict the pulmonary pressure response to high altitude
    Chest, 2015
    Co-Authors: Ryan L Hoiland, Mike Stembridge, Chris K Willie, Joseph Donnelly, Glen E Foster, Kurt J Smith, Nia C S Lewis, Samuel J E Lucas
    Abstract:

    BACKGROUND The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Sp o 2 ) at HA would correlate better than HVR at SL with PASP at HA. METHODS In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min · −%Sp o 2 −1 ) and resting PASP using echocardiography. Both resting Sp o 2 and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21]). RESULTS Compared with SL, Sp o 2 decreased from 98.6% to 80.5% ( P P o 2 or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP ( P o 2 . Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Sp o 2 was not related to PASP in lowlanders at any point (all R 2 ≤ 0.05, P > .50), there was a weak relationship in the Sherpa ( R 2 = 0.16, P = .07). CONCLUSIONS We conclude that neither HVR at SL nor resting Sp o 2 at HA correlates with elevations in PASP at HA.

Mike Stembridge - One of the best experts on this subject based on the ideXlab platform.

  • the overlooked significance of plasma volume for successful adaptation to high altitude in sherpa and andean natives
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Mike Stembridge, Alexandra M Williams, Christopher Gasho, Aimee L Drane, Tony G Dawkins, Francisco C Villafuerte, Benjamin D Levine, Rob E Shave, Philip N Ainslie
    Abstract:

    In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

  • ubc nepal expedition phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude
    The Journal of Physiology, 2019
    Co-Authors: Ryan L Hoiland, Mike Stembridge, Connor A Howe, Howard H Carter, Joshua C Tremblay, Chris K Willie, Joseph Donnelly, David B Macleod, Chris Gasho, Lindsey M Boulet
    Abstract:

    KEY POINTS: Sherpa have lived in the Nepal Himalaya for 25-40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives. We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH. The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema. ABSTRACT: Debilitating side effects of hypoxia manifest within the central nervous system; however, high-altitude natives of the Tibetan plateau, the Sherpa, experience negligible cerebral effects compared to lowland natives at extreme altitude. Phenotypical optimization of the oxygen cascade has been demonstrated in the systemic circulation of Tibetans and Sherpa, likely underscoring their adapted capacity to thrive at altitude. Yet, little is known as to how the cerebral circulation of Sherpa may be adapted. To examine potential differences in cerebral oxygen delivery in Sherpa compared to lowlanders we measured arterial blood gases and global cerebral blood flow (duplex ultrasound) during a 9 day ascent to 5050 m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400 m (-30.3 ± 21.6%; P < 0.01) and 4371 m (-14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modelling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximately 100 mL min-1 (∼17-34%) lower cerebral blood flow in Sherpa compared to lowlanders across ascent to altitude (P = 0.046). To ascertain the role of chronic hypoxia independent of the ascent, Sherpa who had not recently descended were also examined at 5050 m. In these Sherpa, cerebral oxygen delivery was also lower compared to lowlanders (∼22% lower; P < 0.01). We highlight new information about the influence of race and genetic adaptation in the regulation of cerebral oxygen delivery. The lower cerebral oxygen delivery in the Sherpa potentially represents a positive adaptation considering Sherpa endure less deleterious cerebral consequences than lowlanders at altitude.

  • baroreflex control of sympathetic vasomotor activity and resting arterial pressure at high altitude insight from lowlanders and sherpa
    The Journal of Physiology, 2019
    Co-Authors: Lydia L Simpson, Philip N Ainslie, Stephen A Busch, Samuel J Oliver, Mike Stembridge, Craig D Steinback, Jonathan P Moore
    Abstract:

    Key points Hypoxia, a potent activator of the sympathetic nervous system, is known to increase muscle sympathetic nerve activity (MSNA) to the peripheral vasculature of native Lowlanders during sustained high altitude (HA) exposure. We show that the arterial baroreflex control of MSNA functions normally in healthy Lowlanders at HA, and that upward baroreflex resetting permits chronic activation of basal sympathetic vasomotor activity under this condition. The baroreflex MSNA operating point and resting sympathetic vasomotor outflow both are lower for highland Sherpa compared to acclimatizing Lowlanders; these lower levels may represent beneficial hypoxic adaptation in Sherpa. Acute hyperoxia at HA had minimal effect on baroreflex control of MSNA in Lowlanders and Sherpa, raising the possibility that mechanisms other than peripheral chemoreflex activation contribute to vascular sympathetic baroreflex resetting and sympathoexcitation. These findings provide a better understanding of sympathetic nervous system activation and the control of blood pressure during the physiological stress of sustained HA hypoxia. Abstract Exposure to high altitude (HA) is characterized by heightened muscle sympathetic neural activity (MSNA); however, the effect on arterial baroreflex control of MSNA is unknown. Furthermore, arterial baroreflex control at HA may be influenced by genotypic and phenotypic differences between lowland and highland natives. Fourteen Lowlanders (12 male) and nine male Sherpa underwent haemodynamic and sympathetic neural assessment at low altitude (Lowlanders, low altitude; 344 m, Sherpa, Kathmandu; 1400 m) and following gradual ascent to 5050 m. Beat-by-beat haemodynamics (photoplethysmography) and MSNA (microneurography) were recorded lying supine. Indices of vascular sympathetic baroreflex function were determined from the relationship of diastolic blood pressure (DBP) and corresponding MSNA at rest (i.e. DBP 'operating pressure' and MSNA 'operating point'), as well as during a modified Oxford baroreflex test (i.e. 'gain'). Operating pressure and gain were unchanged for Lowlanders during HA exposure; however, the operating point was reset upwards (48 ± 16 vs. 22 ± 12 bursts 100 HB-1 , P = 0.001). Compared to Lowlanders at 5050 m, Sherpa had similar gain and operating pressure, although the operating point was lower (30 ± 13 bursts 100 HB-1 , P = 0.02); MSNA burst frequency was lower for Sherpa (22 ± 11 vs. 30 ± 9 bursts min-1 P = 0.03). Breathing 100% oxygen did not alter vascular sympathetic baroreflex function for either group at HA. For Lowlanders, upward baroreflex resetting promotes heightened sympathetic vasoconstrictor activity and maintains blood pressure stability, at least during early HA exposure; mechanisms other than peripheral chemoreflex activation could be involved. Sherpa adaptation appears to favour a lower sympathetic vasoconstrictor activity compared to Lowlanders for blood pressure homeostasis.

  • chemoreceptor responsiveness at sea level does not predict the pulmonary pressure response to high altitude
    Chest, 2015
    Co-Authors: Ryan L Hoiland, Mike Stembridge, Chris K Willie, Joseph Donnelly, Glen E Foster, Kurt J Smith, Nia C S Lewis, Samuel J E Lucas
    Abstract:

    BACKGROUND The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Sp o 2 ) at HA would correlate better than HVR at SL with PASP at HA. METHODS In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min · −%Sp o 2 −1 ) and resting PASP using echocardiography. Both resting Sp o 2 and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21]). RESULTS Compared with SL, Sp o 2 decreased from 98.6% to 80.5% ( P P o 2 or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP ( P o 2 . Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Sp o 2 was not related to PASP in lowlanders at any point (all R 2 ≤ 0.05, P > .50), there was a weak relationship in the Sherpa ( R 2 = 0.16, P = .07). CONCLUSIONS We conclude that neither HVR at SL nor resting Sp o 2 at HA correlates with elevations in PASP at HA.

Robert Lalonde - One of the best experts on this subject based on the ideXlab platform.

  • SHIRPA as a neurological screening battery in mice
    Current protocols, 2021
    Co-Authors: Robert Lalonde, Mohammed Filali, Catherine Strazielle
    Abstract:

    The SmithKline, Harwell, Imperial College, Royal Hospital, Phenotype Assessment (SHIRPA) is a rapid battery of tests comprising 42 measurements of motor activity, coordination, postural control, muscle tone, autonomic functions, and emotional reactivity, as well as reflexes dependent on visual, auditory, and tactile modalities. Individual scores in SHIRPA are sensitive in detecting phenotypes of several experimental models of neural disease, especially cerebellar degeneration and Alzheimer disease, and combined subscores have been useful in estimating the impact of vascular anomalies and exposure to infectious agents. In cerebellar degeneration, weak forelimb grip, impaired wire maneuver and air righting, and negative geotaxis appear as prevalent features. Most of the measures in the battery are susceptible to change after gene modifications or physiological alterations. SHIRPA can be used both in adult mice and mice in the preweaning period to screen for sensorimotor function and emotional reactivity, not selective attention or memory. © 2021 Wiley Periodicals LLC Basic Protocol: Step-by-step procedure for SHIRPA.

  • neurobehavioral anomalies in the pitx3 ak murine model of parkinson s disease and mptp
    Behavior Genetics, 2016
    Co-Authors: Mohammed Filali, Robert Lalonde
    Abstract:

    Pitx3/ak null mutants are characterized by basal ganglia pathology in a manner resembling Parkinson’s disease (PD), with decline in substantia nigra cell numbers as well as striatal tyrosine hydroxylase expression. Although young adult Pitx3/ak mutants were deficient in motor coordination tests, they were more active than non-transgenic controls in the open-field, unlike PD-related bradykinesia. On the SHIRPA primary screen, the mutants displayed body tremor, hyperactivity in the viewing jar, anomalies in eye morphology as well as a higher degree of hindlimb clasping and myoclonic jumping. Increased hindlimb clasping time and rotorod deficits seen in mutants were also exhibited by mice injected with MPTP, indicating an influence of dopamine on these behaviors.

  • cognitive and non cognitive behaviors in the triple transgenic mouse model of alzheimer s disease expressing mutated app ps1 and mapt 3xtg ad
    Behavioural Brain Research, 2012
    Co-Authors: Mohammed Filali, Robert Lalonde, Peter Theriault, Carl Julien, Frederic Calon, Emmanuel Planel
    Abstract:

    3xTg-AD mutant mice are characterized by parenchymal Aβ plaques and neurofibrillary tangles resembling those found in patients with Alzheimer's disease. The mutants were compared with non-transgenic controls in sensorimotor and learning tests. 3xTg-AD mutants were deficient in T-maze reversal, object recognition, and passive avoidance learning. In addition, the mutants showed hypoactivity in two open-field tests, fewer fecal boli in an observation jar, and reduced enclosed arm entries and head-dipping in the elevated plus-maze. On the contrary, the mutants did not differ from controls in pain thresholds, nest-building, and various reflexes determined by the SHIRPA primary screen and were even better on the rotorod test of motor coordination.

  • neurobehavioral characterization of app23 transgenic mice with the SHIRPA primary screen
    Behavioural Brain Research, 2005
    Co-Authors: Robert Lalonde, M Dumont, Matthias Staufenbiel, C. Strazielle
    Abstract:

    The SHIRPA primary screen comprises 40 measures covering various reflexes and basic sensorimotor functions. This multi-test battery was used to compare non-transgenic controls with APP23 transgenic mice, expressing the 751 isoform of human beta-amyloid precursor protein and characterized by amyloid deposits in parenchyma and vessel walls. The APP23 mice were distinguishable from controls by pathological limb reflexes, myoclonic jumping, seizure activity, and tail malformation. In addition, this mouse model of Alzheimer's disease was also marked by a crooked swimming trajectory. APP23 mice were also of lighter weight and were less inclined to stay immobile during a transfer arousal test. Despite the neurologic signs, APP23 transgenic mice were not deficient in stationary beam, coat-hanger, and rotorod tests, indicating intact motor coordination abilities.

Till Strowig - One of the best experts on this subject based on the ideXlab platform.

  • transgenic expression of human signal regulatory protein alpha in rag2 γc mice improves engraftment of human hematopoietic cells in humanized mice
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Till Strowig, Anthony Rongvaux, Chozhavendan Rathinam, Hitoshi Takizawa, Chiara Borsotti, William M Philbrick, Elizabeth E Eynon, Markus G Manz, Richard A Flavell
    Abstract:

    Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γc−/− (NSG) and BALB/c Rag2−/−γc−/− mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2−/−γc−/− mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2−/−γc−/− mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated.

  • transgenic expression of human signal regulatory protein alpha in rag2 gamma c mice improves engraftment of human hematopoietic cells in humanized mice
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Till Strowig, Anthony Rongvaux, Chozhavendan Rathinam, Hitoshi Takizawa, Chiara Borsotti, William M Philbrick, Elizabeth E Eynon, Markus G Manz, Richard A Flavell
    Abstract:

    Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γ(c)(-/-) (NSG) and BALB/c Rag2(-/-)γ(c)(-/-) mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2(-/-)γ(c)(-/-) mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2(-/-)γ(c)(-/-) mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated.