TRANSFORMING · Expression and neuro-protective function of latent transforming growth factor binding proteins in the central nervous system of Rodent and Human
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-09-01 → 2007-08-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - TRANSFORMING (Expression and neuro-protective function of latent transforming growth factor binding proteins in the central nervous system of Rodent and Human)
The neuroprotective functions of transforming growth factor betas (TGF-ßs) are well established. It has been demonstrated that they play a role in the survival of motoneurons, dopaminergic neurons in the substantia nigra whose loss results in Parkinson's disease and also neurons affected by ischemic insult. TGF-ßs are released from the cells in an inactive form together with binding proteins, which also play a role in the activation of TGF-ßs. With the support of the current Marie Curie International Reintegration grant, we established a molecular biology unit in our Neuromorphological Laboratory, which allowed us to investigate the binding proteins of TGF-ßs called latent TGF-ß binding proteins (LTBPs). We demonstrated that all 4 types of LTBPs are expressed in the brain using RT-PCR technique. We also produced in situ hybridisation probes for LTBPs and demonstrated that all 4 types of LTBPs have specific distributional patterns, which markedly differ from each other suggesting subtype specific functions. LTBPs were found in the hippocampus, an area first damaged by global brain ischemia. High level of LTBP-3 but not the other 3 types of LTBPs is expressed in the substantia nigra suggesting that TGF-ß affecting the survival of dopaminergic neurons binds to LTBP-3. In motoneurons, LTBP-3 and -4 but not LTBP-1 and -2 are expressed. Furthermore, the specific expression of LTBP-2 mRNA in orexin neurons, which we found using double in situ hybridization, raises the possibility that LTBP-2 plays a role in the survival of these neurons. These data were also confirmed using double fluorescent immunolabeling using the custom made antibody we produced against LTBP-2. This finding is particularly important since the loss of hypothalamic orexinergic neurons leads to narcolepsy, a common disorder, which cannot be treated effectively yet. Comparing the distribution of TGF-ßs and LTBPs, we suggest that in the brain, TGF-ß1 binds to LTBP-1, TGF-ß2 binds to LTBP-3, and TGF-ß3 binds to LTBP-3 or LTBP-4. The specific binding relationships allow specific regulatory mechanisms of secretion and activation of different TGF-ßs. This finding can also be utilised in applied science by directing drugs for survival of specifically affected neuron types in ischemic stroke or neurodegenerative disorders.
Data: CORDIS, © European Union
Project objective
Transforming Growth Factor ßs (TGFßs) regulate the formation of the extracellular matrix and the growth and differentiation of various cell types in different organs. Latent TGFß Binding Proteins (LTBPs) are needed for secretion, correct folding and matrix deposition of TGFßs. In the brain, TGFß1 is inducible by ischemia, while ß2 and ß3 are present constitutively in several regions. Strong evidence indicates that TGFß1 has neuroprotective functions. The role and the distribution of LTBPs in the brain are unknown. We assume that the four known members of LTBPs also play a role in the processing of TGFßs in the nervous system. Preliminary in situ hybridisation studies clearly show that LTBPs are present in the rat brain.High LTBP1 expression levels are seen in the medial preoptic area, the anteromedial thalamus and some cortical regions. LTBP2, an exceptional member of the LTBP protein family (no binding to TGFßs) is expressed only in cortical areas, hippocampus, and the perifornical/dorsolateral hypothalamus. LTBP3 exhibits a wider expression profile with the strongest expression in the ventral pallidum, anterodorsal and reticular thalamic nuclei, hippocampus, cortex, red nucleus and the periaqueductal gray.The objective of the application is to initiate a research project on the distribution and function of LTBPs in the brain based on these new preliminary data and my background in histology and molecular biology. Apart from identifying the cells and brain regions that express LTBP-s in rat and human the role of this protein family in endogenous neuroprotective mechanisms will also be investigated using experimental ischemia models in rodents as well as post mortem brain samples of stroke patients. Altogether, this application can provide the foundation for a long-term investigation of TGFßs in the nervous systems and also for the applicant’s reintegration to the European and Hungarian neuroscience as an independent investigator.
Original text from CORDIS.
Participants
- RESEARCH GROUP FOR NEUROMORPHOLOGY OF THE HUNGARIAN ACADEMY OF SCIENCES AND THE SEMMELWEIS UNIVERSITY (OFFICE FOR RESEARCH GROUPS), BUDAPEST, HUNGARY · BUDAPESTCoordinatorCity levelHungary
Links
Data: CORDIS, © European Union