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Understanding death-receptor signaling and physiology in the nervous system: A roadmap for the development of new treatments to neurodegenerative diseases and neurotrauma

Understanding death-receptor signaling and physiology in the nervous system: A roadmap for the development of new treatments to neurodegenerative diseases and neurotrauma

Objective

The aim of this proposal is to elucidate the molecular mechanisms and physiological relevance of death-receptor signaling in the nervous system and to harness this knowledge for the development of novel treatments to neurodegenerative diseases and neurotrauma. The main focus is on the p75 neurotrophin receptor (p75NTR), which is predominantly expressed in the developing nervous system and is highly induced upon different types of adult neural injury. Additional studies on other death receptors, such as DR6, are also described. p75NTR signaling can induce neuronal death, reduce axonal growth and decrease synaptic function, hence there is a good rationale for inhibiting p75NTR in neural injury and neurodegeneration. Recent discoveries from my laboratory have clarified the mechanism of p75NTR activation and provided new insights into the underlying logic of p75NTR signaling, paving the way for a genetic dissection of p75NTR function and physiology. These discoveries have open new avenues to elucidate the molecular mechanisms underlying ligand-specific responses and downstream signal propagation by death-receptors, unravel the physiological relevance of death-receptor signaling pathways in health and disease, and develop new strategies to block death-receptor activity in neural injury and neurodegeneration.

To drive progress in this research area it is proposed to: i) Elucidate the mechanisms by which p75NTR and other death receptors become activated by different ligands and elicit distinct, ligand-specific cellular responses; ii) Elucidate the mechanisms underlying the specificity and diversity of p75NTR signaling and decipher their underlying logic; iii) Elucidate the physiological significance of distinct p75NTR signaling pathways through genetic dissection in knock-in mice; iv) Harness this knowledge to identify and characterize novel p75NTR inhibitors.

This is research of a high-gain/high-risk nature, posed to open unique opportunities in research & development.
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Principal Investigator

Carlos Fernando Ibañez Moliner (Prof.)

Host institution

KAROLINSKA INSTITUTET

Address

Nobels Vag 5
17177 Stockholm

Sweden

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 500 000

Principal Investigator

Carlos Fernando Ibañez Moliner (Prof.)

Administrative Contact

åsa Garmager (Mrs.)

Beneficiaries (1)

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KAROLINSKA INSTITUTET

Sweden

EU Contribution

€ 2 500 000

Project information

Grant agreement ID: 339237

Status

Closed project

  • Start date

    1 June 2014

  • End date

    31 May 2019

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 500 000

  • EU contribution

    € 2 500 000

Hosted by:

KAROLINSKA INSTITUTET

Sweden