Dr. Imam has pursued his dual career interests in the hospital and the laboratory via the NIH Medical Scientist Training Program (MSTP) and Accelerated Research Pathway fellowship in Neonatology. His graduate training included model organism genetics, molecular and developmental biology, and genomics, and his subsequent medical training in the neonatal intensive care unit introduced him to acutely ill premature and term newborn infants. Many of these infants were exposed to environmental perturbations as part of their disease process, such as low oxygen levels causing injury during a critical time of organogenesis and contributing to cerebral palsy, seizure disorders, and cardiac failure. These pathological changes in oxygen and other physiologic factors cause metabolic and cellular stress to the developing brain and heart that disrupt normal function and organ formation. Accordingly, Dr. Imam decided to focus his studies on the problem of hypoxia-induced cellular injury as a means to better understand how cells in the brain and heart become injured, with the ultimate hope of being able to diminish or prevent the end-organ damage from hypoxic stress. Inspired by the desire to improve developmental outcomes for prematurely born infants, Dr. Imam has established and published a robust model to study the protective phenomenon of hypoxic preconditioning. In this zebrafish model, embryos that are exposed to mild or moderate hypoxia are able to recover to a transient protected state during which they can withstand severe hypoxia exposures that would be overwhelmingly lethal for nave embryos. His unique proposal takes advantage of the novel zebrafish system he has developed, including the mutants he has generated in the discovered hypoxia resistance genes. The multitude of cell biological, genetic, and epigenetic tools available for Dr. Imam's zebrafish model empowers his system with a wealth of approaches to determine the biological mechanism of this transient, yet robustly resilient state. Ultimately, Dr. Imam's goal is to translate his discoveries in model organisms into specific therapies that could activate the hypoxic preconditioning response and thereby protect premature infants or adult patients at risk for hypoxia/ischemia against injury to the brain, heart, or other organs. This K08 Award would provide Dr. Imam with the support necessary to pursue the protective mechanisms of the novel hypoxia-protective genes he has discovered with the purpose of moving us closer to new therapies for severe and devastating diseases such as cerebral palsy, stroke and heart attack.
Hypoxia is a major cause of tissue and organ injury and can cause debilitating disease for infants via birth asphyxia and cerebral palsy, or in adults via hear attack and stroke. A widespread, natural protective phenomenon termed 'hypoxic preconditioning' occurs when prior hypoxia exposure results in robust hypoxia resistance, but it is poorly understood.] We have developed a novel animal model of hypoxic preconditioning and propose genetic and genomic investigations in order to better define its protective mechanisms and thereby contribute to novel therapeutic strategies for hypoxia-induced disease in humans.
| Marin-Valencia, Isaac; Novarino, Gaia; Johansen, Anide et al. (2018) A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. J Med Genet 55:48-54 |
