This is a """"""""Midcareer Investigator Award in Patient-Oriented Research: PA-00-005"""""""" entitled Therapeutic Strategies in Disorders of Hematopoiesis. The formation of blood cells represents a complex interaction between stem cells, ceils making up the stromal microenvironment and growth regulatory proteins, which are presented in soluble and localized forms. These interactions give rise to an enormous number and diversity of cells that function in widely separated parts of the body to transport oxygen, defend against infectious agents and provide stimulus for clotting. Abnormalities that impair the process of blood cell development, such as Myelodysplasia and Acute Myelogenous Leukemia (AML); as well as Cancer, can lead to life threatening illness as welt as lineage specific myelosuppression or pancytopenia resulting in significant morbidity and mortality. This proposal focuses on the development, conduct and mentoring of scientifically based, hypothesis-driven pilot clinical investigations, designed to exploit inherent biological features of these specific diseases. Three distinct central hypotheses underlie the Candidate's present (currently funded) and new (to be supported by K24) clinical research efforts: 1) the therapeutic application of agents that interfere or reverse transcriptional repression will be of clinical utility in AML and MDS respectively; 2) inhibition of autocrine and microenvironmentally presented growth factors, which contribute to delays in programmed cell death, characteristic of disorders such as chronic lymphocytic leukemia (CLL), represents a novel therapeutic approach of potential utility; and 3) cytokines inhibitory for erythropoiesis contribute to anemia of cancer; strategies to overcome cytokine inhibition should augment red blood cell production in cancer patients and further reduce the clinical problem of anemia in this population. An important part of this application concerns the active mentorship of key junior faculty and hematology/oncology fellows who have chosen to pursue academic clinical research as a career path. This mentorship program consists of: 1) participation in specific curriculum in conjunction with the NIH funded Clinical Research Training Program (K30), for which the candidate serves as the Principal investigator, and IRB course on conduct in Clinical Research; 2) direct oversight, including weekly meetings for: (a) protocol and IND development; (b) accrual, data and regulatory review; (c) manuscript and presentation preparation.
