Bone marrow failure states, including aplastic anemia (AA) and myelodysplasia (MDS) are disorders characterized by hematopoietic progenitor or stem cell failure resulting in deficient production of one or all blood cell lineages. Immune pathophysiology and propensity for clonal evolution are the unifying factors in these diseases that can be otherwise very heterogeneous. Prior collaborative trials have led to the improvement of effective medical therapy for AA, but the therapeutic options and outcomes in MDS remain very limited. Laboratory and clinical studies are needed to better understand the pathophysiology and etiology of MDS and AA with the goal of development of improved diagnostic tools and treatment approaches. Formation of the Idiopathic Bone Marrow Failure Syndromes and Cytopenia Center, as a part NIH-sponsored Rare Disease Clinical Research Network at the Cleveland Clinic Cancer Center provides a solid research and clinical foundation for this K24 proposal. Cleveland Clinic Foundation consortium of several specialized centers and data and technology coordinating program clearly will facilitate translational and clinical research in these otherwise rare diseases through sufficient patient accrual. Our research plan includes testing of novel diagnostic tools, including serum proteomics biomarker analysis, microarray comparative genomic hybridization and molecular analysis of the clonal T cell repertoire in bone marrow failure syndromes and application of these modern technologies to guide rational design of clinical pilot and phase II trials. Application of standardized diagnostic tests and comprehensive laboratory and clinical analysis will facilitate development of screening protocols and longitudinal studies allowing to query various clinical and pathophysiologic questions. These research activities will serve as a basis for training programs integrating young physician scientists recruited from hematology/oncology fellowship and PhD/MD programs into the clinical and translational research team and stimulate interest in an academic career path as clinical investigator. Our proposal encompasses a multi-targeted approach involving: 1) Systematic evaluation of novel laboratory assays that may improve diagnostic accuracy or understanding of pathophysiologic mechanisms in bone marrow failure; 2) Enrollment of patients into longitudinal follow-up studies to correlate new and established diagnostic variables with outcome data; 3) Development of experimental treatment protocols for disease subsets without good treatment options or without a standard treatment approach, 4) Training of post-doctoral fellows to develop clinical trials and translational research projects within the bone marrow failure center, 5) Integration of the basic scientists into clinical research and physicians from related disciplines to form a productive team conducting research in the field of bone marrow failure syndromes. The expertise of the principal investigator, together with the experience, size and facilities at CCF CC and the newly formed IBMFS&C center uniquely fits with the spirit of the K24 award program and would allow Dr. Jaroslaw Maciejewski to commit more time and effort to clinical research and training while building a strong research program.
Showing the most recent 10 out of 72 publications
