Disruption of the blood-brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. A crucial aspect of the design of treatment protocols to reduce BBB disruption in several brain disorders is the dual nature of the molecules targeted for treatment. Indeed, many of those molecules that participate in neural cell death in the early stages of the injury also have a critical role in the recovery period. For example, the benefit derived from the treatment with matrix metalloproteinase inhibitors in the early stages of brain injury may be lost if the same enzymes are blocked in the later stages when they are used in neurogenesis and neurovascular unit (NVU) angiogenesis. Thus, the challenge to modulate BBB in brain diseases involve the identification of novel molecular signals that allow one to repair the NVU injury and modulate vascular brain permeably without interfering with neural recovery. Recently we discovered that miR-107 targets dicer at the post-transcriptional level during hindbrain neurogenesis to preferentially regulate th biogenesis of the pro-neurogenic miRNA, miR-9 (Ristori E., Dev Cell 2015, in press). miR-107-/- fish, that lack miR-107-dicer-miR-9 regulation, have an increased number of glia progenitors and neurons. We also discovered that miR-107 mutants have a disrupted BBB integrity. How the loss of miR-107 induces breakage of the NVU is not known. Here we propose to study the vascular defect in the miR-107 mutants. miR-107 expression is highly conserved in the human brain under physiological conditions. Importantly, miR-107 levels are decreased in neural pathogenesis such as glioblastoma and upon traumatic brain injury in which increase in neurogenesis and the BBB disruption are common hallmarks. Therefore, studies of miR-107-/- model can provide in the long term a unique window into the events that drive neurogenesis and NVU injury in neurological disorders in which miR-107 expression is lost.

Public Health Relevance

Our studies will lead to the identification of potential attractive approaches to control NVU rupture and modulate BBB permeability without interfering with the pro- neurogenesis phenotype in the miR-107-/-. We aim to so by decipher the dual role of miR-9-signaling in neurogenesis and vascular permeability upon loss of miR-107 function. Our long term goal will be to identify novel therapeutic promise to modulate BBB permeability without interfering with the neurogenesis driven recovery of neurological disorders in which miR-107 is lost.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL130246-02
Application #
9197684
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Galis, Zorina S
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Narayanan, Anand; Hill-Teran, Guillermina; Moro, Albertomaria et al. (2016) In vivo mutagenesis of miRNA gene families using a scalable multiplexed CRISPR/Cas9 nuclease system. Sci Rep 6:32386
Lopez-Ramirez, Miguel A; Calvo, Charles-Félix; Ristori, Emma et al. (2016) Isolation and Culture of Adult Zebrafish Brain-derived Neurospheres. J Vis Exp :53617