DESCRIPTION (provided by applicant): Smad3-Sox17 antigenic signaling underlies vascular instability and germinal matrix hemorrhage. Pediatric stroke, including germinal matrix hemorrhage (GMH), remains an ill-defined and poorly understood construct despite increasing recognition of its public health significance. My development as a clinician scientist and pediatri critical care physician is focused on defining the molecular mechanisms underlying GMH, and to improve the clinical outcomes of children at risk for, and who suffer GMH. My long-term goal is to develop as an academic pediatric neuro-intensives and an independent investigator in developmental neurovascular biology. The central hypothesis of this proposal is that altered antigenic programs due to loss of Smad3-Sox17 cooperation underlie vascular instability and GMH, and that interventions which normalize these programs will protect from GMH. This hypothesis is formulated on the basis of preliminary data presented in this proposal and on previously published work, and will be tested through two Specific Aims: 1) Determine how Smad3 and Sox17 regulate Dll4 expression, and 2) Determine the role of Notch/Dll4 signaling in producing abnormal angiogenesis and GMH. The concept that abnormal angiogenesis leads to GMH is quite innovative, and I will take an innovative approach in the proposed studies, including using novel mouse models and in vivo ChIP-PCR, to delineate the mechanisms of Smad3-Sox17 binding to DNA, and the core downstream transcriptional network underlying vascular dysplasia and GMH. The proposed research is significant because it is expected to advance our understanding of the biology of brain vascular development and the pathophysiology of GMH, and will identify promising new targets for the treatment and prevention of GMH in humans. The training objectives and related research activities of this proposal will provide new skills, manuscripts and pilot data related to brain endothelial gene regulation in mice and humans with GMH, necessary to establish my independence in these areas and obtain R01 funding to advance this unique research program.

PUBLIC HEALTH RELEVANCE: Pediatric stroke, including germinal matrix hemorrhage (GMH), remains an ill-defined and poorly understood construct despite increasing recognition of its public health significance. This proposal is a critical first step towards developing tenable models and therapies addressing the angiogenic component of GMH. We anticipate that this line of research will lead to a better understanding of the mechanisms of GMH and to more efficacious therapies.