The objective of this study is to elucidate the basic mechanisms involved in the regulation of erythropoiesis and to apply this knowledge to human erythropoietic diseases. Erythropoietin appears to have a primary effect on the cytoplasmic membrane of marrow cells to produce an active marrow cytoplasmic factor (MCF) that stimulates nuclear RNA synthesis. The MCF is a protein which has resisted purification because of its marked lability. Experiments will be performed to enhance the stability of the MCF. The MCF will then be purified and the mechanism of its effect on RNA synthesis will be investigated. The polycythemia produced by the Friend virus (FVP) will also be studied. FVP markedly increases erythropoiesis in mice by a mechanism that does not require the presence of erythropoientin. The effect of FVP on the MCF will be measured. The effect of the virus on RNA, DNA, and protein synthesis by the mouse spleen will then be studied to determine if its mechanism of action is similar to erythropoietin. Metabolic inhibitors will be employed to determine the primary effect of FVP. The RNA of FVP treated apleens will be fractionated on sucrose gradients to determine if specific components are synthesized in a manner similar to erythropoietin or whether a different pattern is present. The effect of both FVP and erythropoietin on nuclear polymerases 1 and 2 and on template capacity will be compared and an attempt will be made to infect fetal erythroid cells with the virus in vitro and study the effect on hemoglobin synthesis. The methods developed in these investigations will be applied to the study of polycythemia vera. This human blood disease has many similarities to Friend virus polycythemia of mice: increased red cell production not dependent on erythropoietin and often accompanied by increased white cell and platelet production; splenomegaly; and terminal leukemia. The amount of MCF in polycythemia vera marrows will be measured and compared to the amount in secondary polycythemia marrows. It is conceivable that increased erythropoiesis in this disease is due to an abnormal control of the MCF.