Overall Project SummaryNeonatal hypoxia-ischemia (H/I) remains a major health issue with limited therapeutic approaches. The lifelong consequences to both infant and caregivers demands we increase our knowledge regarding the origins,consequences and prevention of brain damage around the time of birth. Clinical evidence increasingly pointsto the cerebellum as a region that is profoundly but more diffusely impacted by neonatal H/I and this damagereverberates as additional damage ensues to the regions with which it shares reciprocal connections. Yet thecerebellum has been largely ignored in preclinical models of neonatal H/I. This proposal models H/I in the termhuman infant, a time of heightened sensitivity for the cerebellum. Insults that occur during narrow sensitiveperiods can have enduring effects by derailing dynamic developmental processes that can never be reset.Often neonatal H/I is compounded by earlier, and perhaps undetected, neuroinflammation. Thus we propose toconduct an in-depth first-of-its-kind analysis of the developing cerebellum after neonatal H/I with and withoutprior inflammation. We attack the question with three Specific Aims. SA1: Develop an animal model of term H/Iwith and without prior inflammation that has construct validity for clinical evidence of cerebellar damage innewborns. SA2: Integrate neuroanatomical, metabolic, signal transduction and behavioral endpoints relevant tocerebellar damage in this animal model. SA3: Test the neuroprotective effects of agents that inhibitneuroinflammation, restore metabolism and/or prevent dysregulated signal transduction and thereby create apreclinical foundation for translation in the immediate future. These aims will be achieved via four independentprojects and synergy assured by provision of animals, histology and behavioral testing from the Animal andBehavioral Core (Core B). Each project is headed by an expert PI. Project I (McCarthy) - microglia as thebrain's innate immune system and their role in normal cerebellar development and impact on damage, ProjectII (McKenna) - metabolism and its response to and role in damage, and Project III (Bearer) - lipid rafts asessential signaling elements disrupted by H/I and inflammation. Project IV (Waddell), an R03 pilot project,explores the novel use of eye blink conditioning, a well known cerebellar controlled learning paradigm, toassess the cognitive impact of neonatal H/I. Microglia both respond to and produce inflammation which can, ifnot arrested, become a run away and enduring pathological response. Metabolism and energy use is animportant determinant of damage following H/I, with high energy areas at greater risk, including the cerebellum.Use of MALDI-MSI imaging will provide detailed high resolution relevant to lipids, neurotransmitters, oxidativestress and metabolism. Lipid rafts are critical components of neural development yet they have been largelyunexplored in the context of H/I. All experiments include equal numbers of males and females. Together theseprojects will highlight new therapeutic targets that can be easily implemented in current clinical practice.
|Effective start/end date||8/17/16 → 7/31/21|
- National Institutes of Health: $1,278,484.00
- National Institutes of Health
Neural Cell Adhesion Molecule L1
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Reactive Oxygen Species