Your own one- or two-year crystal ball

You may know that for many years one of my jobs at CurePSP is to chair the grant review. Twice a year we have a deadline for researchers in either academia or the private sector to apply for up to $100,000 for work related to PSP or CBD. It’s very competitive, as we receive about 20-25 applications a year from some top research groups and fund only about 5-7 of them. We welcome purely clinical projects as well as laboratory work. The term of the grants is 1 or 2 years. Here are the 4 successful awardees from our Fall 2019 grant cycle:

Lukasz Joachimiak, The University of Texas Southwestern Medical Center, Dallas: Structural basis for tau strain conformation in CBD and PSP

In the brain, the tau protein can form an altered shape that clumps together in an aggregated form.  This study will isolate the tau protein from healthy, PSP, and CBD patient brain tissues. Specialized research tools will be applied to determine how the abnormally folded shape of tau differs from the tau from healthy brains. Understanding the fine details of how the tau protein changes from a normal shape to the different “bad” forms found in disease will provide the blueprint for designing new methods to detect and prevent these devastating diseases in patients.

David Butler, Neural Stem Cell Institute, Rensselaer, NY: Bifunctional intrabodies to lower tau

The goal of this project is to develop therapeutic agents that will prevent tau accumulation and associated death of brain cells with novel antibody-based reagents (termed intrabodies). Intrabodies are antibodies expressed within brain cells, while antibodies produced by the immune system or administered by vein do not penetrate brain cells.   These antibodies are highly selective for tau, and they have been engineered to target tau for degradation using the cell’s normal clearing process. The study’s central hypothesis is that targeted degradation of tau protein will reduce the amount of tau available to misfold and thus reduce cell death.

J. Mark Cooper, University Hospital, London, UK: The influence of TRIM11 on tau, aggregation, release, and propagation

In 2018 this research group identified the TRIM11 gene as a risk factor for PSP. This study will investigate the effects of a the protein encoded by that gene on toxic tau protein aggregation in the brain. It is believed to play a role in regulating the levels of some proteins within the cell, in particular proteins that may form aggregates. The study will use models of brain cells grown in the laboratory to focus on how changes to TRIM11 influence tau protein regulation, in particular its tendency to aggregate. These findings may help to identify potential therapeutic targets to modify PSP disease progression.

K. Matthew Scaglione, Duke University, Durham, NC: Small-molecule regulation of a protein quality-control E3 to treat PSP

The protein Hsc70 or “CHIP” accelerates the removal of tau from the brain. This project intends to identify compounds that stimulate CHIP functions.  One important such function is as an “E3” enzyme, which is an important part of one of the brain cells’ “garbage disposal” mechanisms called the ubiquitin-proteasome system (UPS).  E3 allows the UPS to recognize specific proteins for appropriate disposal.  Finding new compounds to stimulate this function is an important first step toward developing small (that is, orally dosable) molecules to slow or prevent the progression of PSP and CBD.

(If those descriptions sound like they’re not my own writing style, it because each was provided by the researchers themselves and then edited by me to fit what I think, based on little evidence, to be the technical background of this blog’s readers.)

I’ll update you on the progress of those projects once they’re publicly presented or published over the next 2 or 3 years.

A sidebar about PubMed: If you didn’t already know, you can see these, or any, researchers’ previously published work by typing a name into the search line at PubMed. Enter the last name, then the initials. To narrow it down, add a topic (like tau or neurodegenerative disease). The initial display lists papers satisfying the search terms in reverse chronological order. Clicking on one of them brings up the authors, institutions and a half-page, technical-language summary. There’s always a stack of links to related papers, including subsequent ones that cite it. Clicking an author’s name will produce a list of his/her other publications. Plus, for some articles, the whole text is available via a clickable link, sometimes for free, usually for an exorbitant fee. Have fun!

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