Neuroendocrine regulation of erythropoiesis following trauma

Univ Of Med/Dent Of Nj-Nj Medical School, Newark NJ

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Abstract

DESCRIPTION (provided by applicant): This proposal describes a five year training program for the further development of an academic career in Surgery. The principal investigator is currently a faculty member and plans to enhance her scientific skills through an unique integration of interdepartmental resources. The long term goal of this program will evaluate the effects of the neuroendocrine system on erythropoiesis following severe injury. Pranela Rameshwar, PhD will mentor the principal investigator's scientific development. Dr. Rameshwar is a recognized leader in the field of hematopoiesis, stem cells and neuroimmunology. She is an Associate Professor of Medicine and recipient of the Master Educator Award for the training of postdoctoral fellows and graduate students. To enhance this training, this program will also enlist the expertise and mentorship of David H. Livingston, MD, Professor of Surgery. Dr. Livingston has pioneered the study of bone marrow (BM) failure following trauma. Recent work in Dr. Livingston's laboratory has demonstrated that erythropoietic dysfunction occurs following trauma. Acute injury activates the neuroendocrine system and the sympathetic nervous system plays a central role in mediating the counter-regulatory stress response to injury. Sympathetic stimulation accompanies both clinical and experimental trauma as well as hemorrhagic shock and it is known to modulate erythropoiesis under non-stressed conditions. Successful erythropoiesis requires interactions between hematopoietic progenitor cells, BM stroma and the BM microenvironment. The proposed experiments will test the hypothesis that early and persistent adrenergic stimulation of BM after trauma impacts the growth of erythroid cells and contributes to the development of anemia. The specific aims include: 1) Defining alterations in erythropoiesis following modification of adrenergic stimulation, 2) Elucidating the effects of neuroendocrine manipulation on erythroid development and the cellular signaling mechanisms involved, 3) Defining the neuroendocrine effects on BM stroma and BM cytokines. In a rodent model of trauma/hemorrhagic shock with the use of both pharmacologic and surgical models of sympathetic alteration, erythropoiesis will be analyzed utilizing cellular, biochemical and molecular techniques. This proposal is novel and understanding the neuroendocrine mechanism of erythropoiesis following trauma is a preliminary step towards potential therapeutic modalities for the treatment of anemia.