Recent evidence indicates that the rate-limiting step in repair of the demyelinated lesions seen in multiple sclerosis and in infants with hypoxic injury is not the recruitment of new oligodendrocyte progenitors to.the site of the damage, but rather the effective maturation of these progenitors into myelinating oligodendrocytes. To a very large extent, the maturation of oligodendrocyte progenitors is regulated by the bHLH transcription factor Oligl. The long-term objective of the research proposed here is to develop small molecule activators of the Oligl maturational program. 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" we will generate fundamental insights into the molecular mechanisms of Oligl function. We reason that surrogate targets for development of Oligl agonists might well be embedded within the Oligl modifiers, co regulators or downstream genetic targets. With this view in mind, we have three specific aims:
Aim one is to define posttranslational modifications of Oligl protein.
Aim two is to detect proteins that interact with Oligl.
Aim three is to identify direct genetic targets of Oligl The mechanistic insights into Oligl that we seek here are common to all three projects within this POl initiative. The answers to these questions (and economies of scale for the P01 as a whole) will be enabled by an interactive Druggable Mechanisms Core ("DMC"). The DMC provides centralized capabilities for mass spectroscopy, chromatin immunoprecipitation, single molecule ? DNA sequencing ("ChlP/Seq" and "RNA/Seq") and bioinformatics.
In the fullness of time, molecular insights into Oligl function arising from this work could lead to a new generation of therapeutics for adult patients with multiple sclerosis and for children with periventricular leukomalacia - a common precursor lesion of cerebral palsy.
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