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INIZIO_TESTO_DA_INDICIZZARE

RESEARCH PROGRAM

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International Patent Classification
  • CHEMISTRY; METALLURGY
    • BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
      • MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF (biocides, pest repellants or attractants, or plant growth regulators, containing micro-organisms, viruses, microbial fungi, enzymes, fermentates or substances produced by or extracted from micro-organisms or animal material A01N63/00; food compositions A21, A23; medicinal preparations A61K; chemical aspects of, or use of materials for, bandages, dressings, absorbent pads or surgical articles A61L; fertilisers C05); PROPAGATING, PRESERVING OR MAINTAINING MICRO-ORGANISMS (preservation of living parts of humans or animals A01N1/02); MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (micro-biological testing media C12Q)
  • HUMAN NECESSITIES
    • AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
      • ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • MEDICAL OR VETERINARY SCIENCE; HYGIENE
      • PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES (bringing into special physical form A61J [N: mechanical aspects]; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; compounds per se C01, C07, C08, C12N; soap compositions C11D; micro-organisms per se C12N) [C0203]
      • THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
Geographical classification
Keywords
RETINITIS PIGMENTOSA, APOPTOSIS, PHOTORECPTORS, CERAMIDE, ELECTRORETINOGRAM

Antiapoptotic strategies in retinal degeneration: a multidisciplinary approach

Università di Pisa
Abstract
Retinitis Pigmentosa (RP) comprises a group of inherited disorders characterized by the progressive deterioration and death of retinal photoreceptors. Symptoms of typical RP are the development of night blindness and the progressive restriction of the visual field, until all the effective sight is eventually loss. The estimated incidence of RP is of 1:3,500 with no available cure yet. Many laboratories are actively developing strategies aimed at repairing RP or, at least, at slowing down the disease progression. A promising tool to treat this disorder is neuroprotection, that is the attempt to interfere with the pathway of photoreceptor degeneration eventually leading to blindness.
Photoreceptor degeneration in RP takes place by a cellular mechanism called apoptosis. This is a form of active cell suicide, involving the specific execution of a program, whose steps are carefully controlled by the cell, but that can also manipulated from outside.
Our project is centred upon a better understanding of the mechanism leading photoreceptors to apoptosis in RP. In particular, we have preliminary data supporting the hypothesis that the sphingolipid ceramide, a powerful molecule leading to neuronal apoptosis in Alzheimer, Parkinson and Batten diseases, is also involved in photoreceptor degeneration in RP.
We want to demonstrate that it is possible to rescue degenerating photoreceptors in animal models of RP by using drugs which prevent the synthesis of this, very >>>

Principal Investigator
Maria Claudia Gargini Università degli Studi di PISA
Research Objectives
Final objectives of this proposal are to understand the role of sphingolipid mediators in the initiation and progression of Retinitis Pigmentosa and to attempt a novel pharmacological approach to the treatment of inherited retinal degenerations.
The underlying assumption to be tested by the proposed study is that, independently of the genetic defect triggering retinal degeneration, the final common patway leading to cell apoptosis involves an alteration of the sfingolipid metabolism.
Preliminary results to be confirmed and extended suggest that in the rd10 mouse, a mutant carrying an autosomal recessive defect that leads to complete death of rod photoreceptors by P30, the levels of newly synthetized ceramide are increased with respect to wild type (wt) mice.
In order to achieve the proposed objectives, the coordinated efforts of the three units shall be directed towards the following specific aims:
a) to validate preliminary data demonstrating that ceramide levels increase progressively in the retina of rd10 mice concurrently with the progression of the disease and compare these data to ceramide levels in wt mice of different ages.
b) to asses whether myriocin, an inhibitor of the rate limiting step of de novo ceramide synthesis catalyzed by serine-palmitoyl transferase (SPT), and fumonisin b1, inhibitor of a different step of the same pathway, catalyzed by sphingosine N-acyl transferase, are able to reduce ceramide accumulation in the rd10 >>>

First Results
This projects aims at demonstrating an involvement of the sphingolipid transduction system in the apoptotic death occurring in inherited photoreceptor degeneration of mammals; this leads to the immediate perspective of devising new therapeutic strategies to treat Retinitis Pigmentosa by targeting the sphingolipid pathway.

The proposed research can reveal the role played by the sphingolipid signalling pathway in Retinits Pigmentosa, a family of inherited disorders leading to blindness and so far without a cure. Although it is known that photoreceptor degeneration in RP is apoptotic, intracellular pathways triggering and executing the apoptotic cascade are still largely unknown. Each molecular player of these pathways represents a potential target for anti-apoptotic strategies aimed at slowing down photoreceptor death. It is to note that, albeit the efficacy of antiaptotic strategies might be considered limited in systems in which the pro-death stimulus persists, such as in the case of genic mutations, such strategies could be effective in treating slow-progression diseases, like RP. Considering that, in typical RP, the degeneration of rod photoreceptors takes years to complete, a further slow down of the photoreceptor demise process would represent a beneficial increment in the preservation of useful residual vision. Moreover, knowing that cones depend upon rods for their survival, the increased lifetime of rods would play a secondary, neuroprotective action >>>

Timescale
24 months
National and international background
Apoptotic programmed cell death is recognised to play an important role in various neurodegenerative disorders, including Parkinson's disease (PD) and amyotrophic lateral sclerosis(ALS), as well as in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) (reviewed in Waldmeier, 2003). In recent years, the strategy of using antiapoptotic drugs for therapeutic benefit in neurodegeneration has gained credit. Biochemical and cell biological studies have greatly contributed at sorting out the pathways involved in
apoptosis, opening the perspective of designing compounds that interfere with disease processes without otherwise adverse effects. In several animal models, functional deficits caused by apoptotic cell death can now be delayed or at least partially prevented by antiapoptotic treatments (i.e. Sugai et al., 2004). Although much remains to be done in the area of exploring the potential of antiapoptotic drugs, the prospect that antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is generally judged quite positively. Such compounds are expected to slow progression of chronic neurodegenerative diseases rather that exhibiting acute symptomatic effects.
Among the affections of the Central Nervous System in which apoptotic cell death plays a relevant role is Retinitis Pigmentosa (RP), a group of hereditary disorders involving the >>>