This proposal outlines a 5-year career development plan for Ryan M. O'Connell, Ph.D.,that begins with a 2 year mentored period and finishes with 3 years of independent researchupon obtaining a tenure track position at an academic institution. The principal investigator(P.I.) has undergone 3 previous years of training as a postdoctoral scholar in the laboratory ofDavid Baltimore, Ph.D., at the California Institute of Technology where significant researchprogress has been made in the field of miRNAs and the immune system. During the mentoredphase of the proposed project, the P.I. will continue to work in Dr. Baltimore's laboratory andreceive additional guidance in specific areas important for carrying out the proposed researchagenda. The proposed work will next be completed during the independent period. The overallscientific goal of this proposal is to understand how mammalian hematopoiesis is regulated bymicroRNAs during inflammatory stress. This research direction is supported by compellingpreliminary data, and the overwhelming medical need to understand how hematopoietic stresscontributes to diseases such as cancer, anemia, immunodeficiency, and autoimmunity. The P.I.has previously identified a specific microRNA, miR-155, that is induced in the hematopoieticsystem during inflammation and sufficient to cause a myeloproliferative disorder upon itssustained expression in the hematopoietic system. Therefore, the central hypothesis to betested is whether physiologically regulated miR-155 promotes myeloid expansion duringinflammation, and does so by directly repressing SHIP1 and selecting specific C/EBP proteinisoforms to be expressed. Results will determine whether miRNAs regulate hematopoiesisduring physiologically relevant inflammatory stress, and provide a mechanistic basis for thisfunction. Furthermore, important insights will be gained regarding how miRNAs can serve aslinks between inflammation and hematological disorders.
Promising advances in biomedical research indicate that both inflammation and microRNAs contribute to human diseases of hematological origins such as cancer, anemia and autoimmunity. This proposal will therefore examine the interplay between inflammation and miRNAs in the context of regulating hematopoiesis, and define a mechanistic basis for this novel function of miRNAs.
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