Grant: Foundation Grant

<html> <body> <p>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite genetic heterogeneity of ALS, a common hallmark is the presence of TDP-43 protein accumulations in degenerating neurons. My laboratory has generated transgenic mouse lines that develop pathological features of ALS including TDP-43 aggregation. Using these transgenic mice, the first aim of my research program will be to elucidate mechanisms that contribute to the onset and spreading of TDP-43 &ldquo;proteinopathy&rdquo;. Based on our discoveries that TDP-43 is a binding partner of the p65 subunit of NF-&#x03ba;B and that inflammation can induce TDP-43 accumulations, we propose to clarify the role of NF-&#x03ba;B pathway by the creation of TDP-43 transgenic mice with cell type-restricted expression of a suppressor of NF-&#x03ba;B. An important effort will also be devoted to investigate the prion-like propagated protein aggregation in TDP-43 proteinopathy. To accelerate protein&nbsp;aggregation and disease, we will produce double transgenic TDP-43^A315T mice co-expressing UBQLN2^P497H, another ALS-linked gene. To study the <em>in vivo</em> effects of the C9orf72 expansion repeats on NF-&#x03ba;B activity and formation of protein inclusions, we will administer AAV vectors bearing expansion repeats into TDP-43 transgenic mice. The role of exosomes in the intercellular transfer of pathogenic TDP-43 will also be examined. In addition, based on our recent discovery that chromogranin CHGB^P413L allelic variant is a gender-specific factor modulating disease onset in ALS, we will&nbsp;study&nbsp;the effect of this genetic variation on TDP-43 proteinopathy by the creation and characterization of double transgenic mice co-expressing TDP-43^A315T and CHGB variants.<br> <br>The second aim is to develop innovative treatment for ALS based on our discovery of new therapeutic targets. Our focus in the near future will be on small molecules and single chain antibodies (nanobodies) to target TDP-43 protein interactions and NF-&#x03ba;B activity. In collaboration with a company, we have already developed novel semi-synthetic withanolides which are potent NF-&#x03ba;B inhibitors. Preclinical studies with two lead compounds are now in progress with the plan to move one compound to Phase I clinical trial. In addition, we&nbsp;collaborate with the <i>Centre for drug research and development</i>&nbsp;in Vancouver to&nbsp;establish an ELISA-based assay for a high-throughput screen of small molecule inhibitors of TDP-43-p65 interaction. Once available, the identified compounds will be tested for their ability to suppress NF-&#x03ba;B and preclinical studies will be carried out with the most promising lead compounds. It is our hope that a nanobody and/or small molecule targeting TDP-43 interactions will eventually move to clinical trial with our&nbsp;collaborators in the <em>Canadian ALS Research Network</em>.<br> <br>This program will be carried out by 2 Ph.D. students and 2 post-doctoral fellows. Each trainee will be responsible for specific projects and will use multidisciplinary approaches with access to state-of-the art technologies. The trainees will participate and speak at lab meetings each week. All facilities, equipment and expertise are available in my laboratory or within IUSMQ to carry out the proposed experiments. IUSMQ is an outstanding scientific environment for trainees: high degree of collegiality, weekly seminars involving world class speakers, availability of technical platforms of new imaging technologies, pathogen-free&nbsp;mouse facility etc.&#xfeff;</p> </body> </html>