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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS047572-10
Application #
8532046
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$272,359
Indirect Cost
$65,933
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Mardinly, A R; Spiegel, I; Patrizi, A et al. (2016) Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531:371-5
Lou, Shan; Pan, Xiaoxin; Huang, Tianwen et al. (2015) Incoherent feed-forward regulatory loops control segregation of C-mechanoreceptors, nociceptors, and pruriceptors. J Neurosci 35:5317-29
Labidi-Galy, S I; Clauss, A; Ng, V et al. (2015) Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. Oncogene 34:373-83
Doherty, Michael F; Adelmant, Guillaume; Cecchetelli, Alyssa D et al. (2014) Proteomic analysis reveals CACN-1 is a component of the spliceosome in Caenorhabditis elegans. G3 (Bethesda) 4:1555-64
Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20
Ficarro, Scott B; Biagi, Jessica M; Wang, Jinhua et al. (2014) Protected amine labels: a versatile molecular scaffold for multiplexed nominal mass and sub-Da isotopologue quantitative proteomic reagents. J Am Soc Mass Spectrom 25:636-50
Bergthold, Guillaume; Bandopadhayay, Pratiti; Bi, Wenya Linda et al. (2014) Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 1845:294-307
Lim, Sang Min; Westover, Kenneth D; Ficarro, Scott B et al. (2014) Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew Chem Int Ed Engl 53:199-204
Lu, Yu; Loh, Yuin-Han; Li, Hu et al. (2014) Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell 15:92-101
Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87

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