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Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis of High Altitude
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A2366 - Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis of High Altitude
Author Block: P. Azad1, G. G. Haddad2; 1Pediatrics, University of California San Diego, La Jolla, CA, United States, 2Univ of California San Diego, La Jolla, CA, United States.
Rationale: Since polycythemia is a predominant trait in some high altitude dwellers (Chronic Mountain Sickness, CMS, or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human “experiment in nature” and studied both populations (with CMS and without, non-CMS). Methods: In order to understand the molecular basis for polycythemia of high altitude, we generated a disease in-the dish-model by re-programming fibroblasts from CMS and non-CMS subjects. In the past, we have discovered that there are selective sweeps that seem to be statistically different between CMS and non-CMS and hence contain candidate genes. In this study, by manipulating expression of these candidate genes (Eg. SENP1, ARID1B) in our in-vitro model system, we delineate the molecular mechanism(s) of the CMS polycythemia.. Results: As compared to sea level controls who responded to hypoxia by increasing their RBCs modestly, CMS cells increased theirs remarkably (up to 60 fold) with a dose-dependent response to graded hypoxia (1.5, 5, 10% O2). Non-CMS cells showed a blunted increase in RBC production under hypoxia. In order to understand the genetic basis of these phenotypes, we knocked down SENP1 (a desumoylase) in CMS iPS cells using lentiviral constructs and observed a striking reduction (>90%) of the CMS excessive erythropoietic response to low O2. Similarly, by knocking down ARID1B in non-CMS we observed that RBC formation increased significantly under hypoxia. Conclusion. Our results demonstrate the presence of a regulatory system (SENP1 and ARID1B) that is critical in erythropoiesis and that is out of balance in the CMS subjects. Further, by combining iPS technology and genomics, we believe that we will be able to determine a comprehensive model of the basis for hypoxia-induced polycythemia. This study is funded by National Institutes of Health (NIH) grants (1P01HL098053 and 5P01HD32573) to G.G. Haddad
Author Block: P. Azad1, G. G. Haddad2; 1Pediatrics, University of California San Diego, La Jolla, CA, United States, 2Univ of California San Diego, La Jolla, CA, United States.
Rationale: Since polycythemia is a predominant trait in some high altitude dwellers (Chronic Mountain Sickness, CMS, or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human “experiment in nature” and studied both populations (with CMS and without, non-CMS). Methods: In order to understand the molecular basis for polycythemia of high altitude, we generated a disease in-the dish-model by re-programming fibroblasts from CMS and non-CMS subjects. In the past, we have discovered that there are selective sweeps that seem to be statistically different between CMS and non-CMS and hence contain candidate genes. In this study, by manipulating expression of these candidate genes (Eg. SENP1, ARID1B) in our in-vitro model system, we delineate the molecular mechanism(s) of the CMS polycythemia.. Results: As compared to sea level controls who responded to hypoxia by increasing their RBCs modestly, CMS cells increased theirs remarkably (up to 60 fold) with a dose-dependent response to graded hypoxia (1.5, 5, 10% O2). Non-CMS cells showed a blunted increase in RBC production under hypoxia. In order to understand the genetic basis of these phenotypes, we knocked down SENP1 (a desumoylase) in CMS iPS cells using lentiviral constructs and observed a striking reduction (>90%) of the CMS excessive erythropoietic response to low O2. Similarly, by knocking down ARID1B in non-CMS we observed that RBC formation increased significantly under hypoxia. Conclusion. Our results demonstrate the presence of a regulatory system (SENP1 and ARID1B) that is critical in erythropoiesis and that is out of balance in the CMS subjects. Further, by combining iPS technology and genomics, we believe that we will be able to determine a comprehensive model of the basis for hypoxia-induced polycythemia. This study is funded by National Institutes of Health (NIH) grants (1P01HL098053 and 5P01HD32573) to G.G. Haddad
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