LAB PROJECTS
CNS vascular development and stability
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The CNS vasculature is vital to brain health and function, providing nutrient and gas exchange to the most metabolically active organ in the body and protecting the CNS from potentially damaging blood contents. Specialized features of the CNS vasculature, including a high density capillary plexus and the blood brain barrier (BBB), are established co-incident with pre- and postnatal brain development. These features must be actively maintained throughout life for normal CNS function. We are interested in the cellular and molecular mechanisms underlying CNS angiogenesis and BBB acquisition during development and in the adult brain. To test our hypotheses, we use transgenic mouse models and cultured primary and brain endothelial cell lines. Currently, we are focused on 1) key endothelial signaling pathways like retinoic acid signaling, WNT signaling and the transcription factor Sox17 and 2) factors that regulate development and recruitment of a vascular support cells, pericytes.
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lightsheet image of vasculature in a E12 cerebral hemisphere
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Meninges-CNS signaling
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The meninges that surround the brain and spinal cord are more than just a protective covering. This structure is an important source of developmental cues that helps regulate neuronal migration, cell positioning and neurogenesis. Furthermore, it contains 1) a vascular plexus that supplies the microvasculature within CNS tissue, 2) neuro-inflammatory cells and 3) neural stem cells and 4) the brain lymphatic vascular system. We study the developmental mechanisms underlying meninges formation using Foxc1 mutant mice that fail to form meninges. We want to understand how Foxc1 regulates the expansion of the meningeal layers around the developing forebrain. We study the meninges as a key source of signals like retinoic acid and others that help regulate developmental and adult neural stem cells and neurogenesis and brain vascular development.
To aid in out study of the meninges, we have generated a single cell transcriptome atlas of embryonic mouse meningeal fibroblasts (see 'Meninges single cell data set' tab to browse our data set). This study demonstrated that layer specific markers for pia, arachnoid and dural fibroblasts emerge early in embryonic development. This work sets up several new questions about how meningeal fibroblast subtypes obtain layer (ex: arachnoid barrier cells) and regional identity and how fibroblast populations in different parts of the CNS (meninges, choroid plexus and perivascular spaces) locally differentiate in their respective structure. |
adult hippocampal stem cells labeled with Nestin-CreErt2 (red), GFAP (blue) and Sox2 (green). NSCs lie with ~200 microns from the hippocampal meninges
scRNA-seq of the embryonic meninges reveal layer and regional heterogeneity in meningeal fibroblast populations
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CNS barrier instability in disease
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CNS disease or injury is frequently accompanied by vascular instability which causes or exacerbates neuronal cell death, edema, and neuro-inflammation. Breakdown in the BBB is a common feature of vascular instability but can also be characterized by vascular dysplasia and loss of blood vessels that lead to insufficient tissue perfusion and hypoxia. Other CNS barriers, specifically the blood-CSF barrier (B-CSFB), in the meninges (arachnoid barrier layer) and choroid plexus are also vulnerable to breakdown in disease but the mechanism are not extensively studied. We study the mechanisms underlying vascular and meningeal barrier instability in disease, specifically ischemic stroke, viral encephalitis and bacterial meningitis. We are interested in the signaling pathways that trigger loss of barrier features, including tight-junctional disorganization.
We also study the response of other perivascular cell types to injury and disease. In our stroke studies, we focus on pro-fibrotic perivascular fibroblast (PVFs) characterized by expression of Collagen-1a1. These cells are sparse in the adult brain but after brain or spinal cord injury, these cells become activated, rapidly proliferate, detach from the perivascular space and deposit extracellular matrix proteins into the lesion area that contributes to fibrotic scarring. We are studying the 1) mechanisms that underlie PVF activation following injury and 2) how signals released by activated PVFs contribute to injury pathology and recovery. |
Progressive activation of Collagen-1a1+ PSCs following stroke injury
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