This is the competing renewal of a program project grant on transcription factors and neurogenesis In the vertebrate central nervous system (CNS). Our long-term goal is to develop small molecule inhibitors and activators of these transcription factors - initially for scientific purposes and ultimately for therapeutic purposes. Transcription factors per se are generally considered to be unattractive targets for drug development because their interactions with DNA and heterodimeric partner proteins involve large and complex surface area contacts. Towards """"""""drugging the undruggable"""""""" a central theme of our program will be identification of surrogate targets for transcription factor drug development at the level of i) co-regulator proteins, ii) post-translational modifications and iii) downstream genetic targets that are essential to the function of our transcription factors. In project one, Dr David Rowitch and I will apply this three-pronged attack to the bHLH transcription factor Olig1. The work we propose builds upon recent insights into the repair of the demyelinated lesions seen in adult patients with multiple sclerosis and in infants with hypoxic injury is the maturation of oligodendrocyte progenitors in response to an Olig1-mediated program of gene expression. In project two, Dr. Qiufu Ma will build on his previous work showing that the runt domain transcription factor Runx1 is a master regulator in the formation of nociceptic neurons that underlie chronic pain syndromes. Dr Ma will define i) direct genetic targets of Runx1 that mediate the perception of chronic pain and ii) upstream signaling pathways that regulate Runxl expression. In project three, Dr Michael Greenberg will build upon his important recent observations that link experience-based inhibitory synapse formation to a specific transcription factor (NPAS4). Greenberg will use Npas4-deficient mouse strains to investigate the role of Npas4 in cortical inhibitory synapse development in vivo and go on to identify and characterize Npas4 targets that control inhibitory synapse number Within the Program Group, scientific synergism is enabled by complementary skill sets in the areas of molecular genetics (CS), developmental neurobiology (QM, MG) and mouse modeling (DR). Economies of scale are afforded by an interactive Druggable Mechanisms Core (""""""""the DMC"""""""") that provides centralized capabilities for mass spectroscopy, chromatin immunoprecipitation, single molecule DNA sequencing (""""""""ChlP/Seq"""""""" and """"""""RNA/Seq"""""""") and bioinformatics.
The work proposed in project one could be of practical value in treating adult patients with multiple sclerosis and children with periventricular leukomalacia - a common precursor lesion of cerebral palsy. Studies described in project two could lead to new drugs for the management of chronic pain. Insights into the genetic targets of Npas4 (project 3) could ultimately have practical overtones in the management of cognitive disorders (autism, schizophrenia) and epilepsy.
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