Huntington's disease (HD) is a devastating, neurodegenerative disease that typically strikes in midlife and is caused by a CAG repeat expansion within the coding region of the HD gene. Due to the genetic basis of HD, unique opportunities exist to model the disease and extend scientific findings to other neurodegenerative diseases. Currently, there is no disease modifying treatment for any neurodegenerative disease, therefore it is critical to elucidate the cellular and molecular mechanisms leading to pathogenesis. Studies have primarily focused on studying the internal signals which prompt neuronal loss; however each cell in the neurovascular unit (NVU) plays a vital role in controlling homeostasis of the CNS and blood brain barrier (BBB) integrity. Utilizing induced pluripotent stem cell (iPSCs) technologies, one can generate in vitro models of HD neurons and other cells of the NVU, including brain endothelial cells (BECs) and astrocytes. Recent evidence of elevated arteriolar cerebral blood volume in HD patients, and increased vascularity in a mouse model of HD, suggests that the NVU and BBB may contribute to HD pathology. However understanding the specific genes involved and how they affect BBB functionality remain to be elucidated. It is known that Shh, Wnt, ApoE, and Ang-I/II signaling maintain homeostasis of the NVU; however, the specific contributions of these signaling pathways are not yet clear, especially in response to disease. It is important to note that both Shh and Wnt signaling, two pathways utilized by astrocytes and BECs in the NVU, are implicated in HD. We therefore hypothesize that abnormal signaling exists in and between BECs, astrocytes and neurons which causes abnormal expression of BBB proteins and contributes to neuronal dysfunction and pathogenesis in HD. Here we will examine if alterations in signaling and transcription exist between the cellular subunits of the NVU, and how this may affect BBB maintenance and subsequently induce neuronal damage in HD. We will utilize patient-derived iPSCs and computational biology approaches to create a model of the NVU in HD; focusing on the signaling between BEC and astrocytes.
Specific Aims are to:
Aim 1 : Determine the contributions of gene networks and cell types in the NVU to disruption of the BBB using HD and control iPSCs.
Aim 2 : Examine the BBB in an in vivo murine model of HD.
Huntington's disease (HD) is a devastating, inherited neurological disorder that causes psychiatric, cognitive and movement deficits. The effects of disease on the brain vasculature and on function and structure of the blood brain barrier are not well understood. This proposal will use an innovative approach to examine signaling pathways involved in brain vascular function and potential dysregulation during HD using patient derived stem cells and in vivo models.
|Lim, Ryan G; Quan, Chris; Reyes-Ortiz, Andrea M et al. (2017) Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits. Cell Rep 19:1365-1377|