Direct inhibition of mutant K-Ras for the treatment of cancer
DESCRIPTION (provided by applicant): There are 5 million births in the United States each year of which 500,000 are premature. Prematurity is associated with substantial mortality, morbidity, and escalating cost. The complications of premature birth include respiratory, gastrointestinal, and central nervous system morbidity, and significant mortality. Many of these complications are caused, directly or indirectly, by our attempts to ventilate the immature lungs and reverse fetal circulation. Although manyof these babies recover with conventional management, the mortality and morbidity of extremely low gestational age newborns (ELGANs) defined as born more than 3 months before the expected date of birth, is very high. The current approach of positive pressure gas ventilation carries high risks of mechanical trauma and oxygen toxicity to the lungs. A major paradigm shift in the post-natal treatment of prematurity would be to avoid the complications of positive pressure ventilation and recreate the fetal environment with an Artificial Placenta (AP) which consists of four unique features: 1) maintaining fetal circulation and environment; 2) no mechanical ventilation; 3) simulated fetal breathing with fluid filled lungs; and 4) a novel form of a pump-driven veno-venous extracorporeal life support (VV-ECLS) circuit with inflow via the umbilical vein and outflow via the right internal jugular vein. Our collaborators at the University of Michigan Extracorporeal Life Support Lab (ECLS Lab) have demonstrated feasibility and reproducibility of complete extracorporeal support with medical components to simulate an artificial placenta for up to 7 days with hemodynamic stability, excellent gas exchange, stable cerebral perfusion, and maintenance of fetal circulation without mechanical ventilation. The goal of this research project is to design and produce an integrated system that will function as an Artificial Placenta for the post-natal treatment of very premature infants (lt28 weeks gestational age). Our system will support ELGANs in the most natural state (i.e., fetal circulation), and is truly innovative and offers many therapeutic opportunities when compared to current clinical practice with mechanical ventilation. Phase l aims include integration of the MC3 BioLung and MPump devices with cartridge heat modules and an automated sweep gas controller. The system will be coated with our unique nonthrombogenic NO secreting polymer to decrease or eliminate the need for systemic anticoagulation. The prototype system will befabricated and tested in vitro to demonstrate safety, efficacy and durability. A pilot in vivo study will be conducted to demonstrate effective fetal circulation. Phase ll will include extended in vivo testing of AP for safety and efficacy, and the development of a clinical ready device. The University of Michigan Extracorporeal Life Support Lab and MC3 are the leaders in this field and can bring this technology to reality in four years. This project has high translational potential and would impact substantially upon the care of high risk premature newborns. Successful completion of this research will lead to a clinical trial in moribund premature infants. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The goal of this research project is todesign, produce, and test an integrated system that will comprise an Artificial Placenta (AP) for the post-natal treatment of very premature infants (lt28 weeks gestational age). This proposal has high translational potential and would impact substantiallyupon the care of high risk premature newborns.
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