ICTS

Sarah Hernandez

Section 1

hernandez

[Name]: Sarah Hernandez

[Department]: Neurobiology & Behavior

[Mentor]Leslie Thompson





Summary:

Huntington’s disease (HD) is a progressive, neurodegenerative disorder caused by a genetic expansion of a CAG repeat encoding glutamine within the huntingtin protein. Individuals with 40 or more glutamines will eventually develop HD. HD is devastating, causing atrophy of the brain, uncontrollable movements, psychiatric disturbances, and behavioral changes. The extracellular matrix (ECM) is a highly plastic component of the cellular environment, continuously being remodeled by architectural modifications that guide cell attachment, cell motility, and cell survival. In the brain, the ECM can provide neuroprotection and loss of certain ECM components leads to phenotypes commonly observed in neurodegenerative diseases. Additionally, perturbations of the ECM can alter synaptic plasticity in the adult brain. And while there is clear evidence regarding the importance of ECM participation in critical CNS functions and neuronal dynamics, little is known about the role of the ECM in neurodegenerative diseases, including HD. Additionally, ECM molecules have shown great promise as highly druggable targets for diseases associated with traumatic neuronal loss. Therefore, taking advantage of the malleability of the ECM and the influence it has on neural plasticity through exogenous introduction of ECM molecules or agonists may allow for the prevention or reversal of disease-associated changes in the HD brain. Identification of ECM disease regulators provides molecular targets that can then be perturbed within cellular systems to elicit disease-modifying effects.


To understand these processes in human cells across a range of human subjects, we are using induced pluripotent stem cells (iPSCs) to study HD by providing a source of patient-derived cells of varying polyglutamine lengths. We're exploring HD-related ECM dysregulation in two iPSC-derived cell types: 1) medium spiny neurons (MSNs) and 2) brain microvascular endothelial cells (BMECs). In MSNs, RNAseq data implicates a dysregulation of ECM-related genes and current work is focused on defining the MSN secretome. Our lab has recently published data suggesting that iPSC-derived BMECs demonstrate an HD-related increase in angiogenesis and reduced barrier properties, implicating blood-brain barrier (BBB) deficits in HD. In BMECs, RNAseq data also demonstrates ECM dysregulation. Current work focuses on exploring the relationship between the ECM, adhesion, and angiogenesis for identification of specific ECM-related molecules that can be modulated ameliorate HD phenotypes and restore BBB dysfunction.


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