Understanding vascular aging-related dementia through medin signaling - Abstract
Age is the most important risk factor for cardio-cerebrovascular diseases and dementia disorders.
Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with dementia
disorders, including Alzheimer's disease (AD) and AD-related disorders such as vascular dementia (VaD). The
mechanistic links among vascular disease, aging and dementia remain poorly understood. There is
growing evidence that medin, a 50-amino acid peptide that forms one of the most common yet least studied
human amyloidoses, is an important driver of vascular aging pathologies. Medin accumulates in the vasculature
with aging and is implicated in AD, VaD and aortic disease. Little is known as to the mechanisms by which medin
induces cell and tissue injury, and no animal model of medin pathology currently exists. We showed that medin
impaired endothelial function and cell viability and induced pro-inflammatory activation, in part through receptor
for advanced glycation endproducts (RAGE). Our goals are to discover biological pathways of medin
toxicity using novel genome-wide CRISPR/Cas9 knockout genetic screening, test F(BA)S peptide and
RAGE knockout to reverse medin toxicity and test the in vivo role of medin in vasculo-neuropathology
by creating a mouse model with endothelial overexpression of medin. In Aim 1, we will probe toxic signaling
mechanisms using a synthetic lethality-based genome-wide CRISPR/Cas9 screening in endothelial cells. This
will generate a list of candidate genes/pathways that facilitate or protect against medin toxicity and could
be potential drug targets. In Aim 2, we will test if peptide F(BA)S can reverse medin toxicity in cultured
endothelial cells and ex vivo in isolated human donor human cerebral arteries. In Aim 3, we will test in vivo the
role of medin in aging-induced vascular and cognitive dysfunction and assess whether RAGE knockout will be
protective. In an exploratory subaim, we will create a transgenic mouse model of endothelium-specific medin
overexpression. Once successfully implemented, the proposal will shed light on the mechanisms
underlying medin vasculo-neuropathology and create a valuable and novel preclinical animal model of
vascular aging that can be used to identify and test new drug targets.
