Project Details
Description
Project Summary
The overall goal and singular focus of our proposed Center Without Walls is to unravel the
mechanisms of FTLD-TDP. We have formed a diverse interdisciplinary team to tackle this
challenge. Our team brings together experts in genetics, genomics, neuroscience, neurology, and
pathology. We have FTLD experts as well as outsiders who bring new perspectives and key
resources and approaches to the field. Our team has also recently made an unexpected discovery
of a new splicing target of TDP-43, which provides a direct and surprising connection to FTD
human genetics and will be a launching pad for defining the mechanisms of FTLD-TDP. We posit
that mis-splicing events caused by TDP-43 dysfunction may well be the earliest events in the
process. Our vision is to create a Center dedicated to providing unprecedented access to TDP-
43 function, even before it is depleted from the nucleus. Rather than have human genetics as an
afterthought or addendum, we endeavor to have the genetics deeply integrated in our program
from Day 1. Our Center will make all of the data and code we generate freely available via a web
portal that contains high resolution images of human brains across different subtypes of FTLD-
TDP showing, at cellular resolution, TDP-43 localization along with a panel of cryptic splicing
readouts as sensitive beacons of TDP-43 activity in different brain regions. This will empower the
broad FTLD research community to generate (and test) new hypotheses about disease
mechanisms and to have at their disposal sensitive biomarkers. Our Center will launch multimodal
efforts to 1) comprehensively discover the TDP-43 splicing targets relevant to human FTLD-TDP;
2) define the mechanisms by which TDP-43-dependent cryptic exon splicing events contribute to
neurodegeneration, using model systems and human tissues; 3) harness these novel cryptic
exons to generate highly sensitive and specific biomarkers for the FTD field; 4) innovate genomics
analysis methods to integrate human genetics data and RNA sequencing data and make these
resources available to the community to discover how genetic risk factors for FTD contribute to
cryptic exon splicing and vice versa. We strongly suspect that we will discover the cryptic exon
splicing code that serves as the Achilles’ heel to drive neurodegeneration in FTLD-TDP.
Status | Active |
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Effective start/end date | 9/15/21 → 8/31/24 |
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