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Transcriptie 1 Inventaris Wob-verzoek W wordt verstrekt weigeringsgronden nr. The appendix 'description animal procedures' is an appendix to this form. For each type of animal procedure, a separate appendix 'description animal procedures' should be enclosed For more information on the project proposal, see our website Or contact us by phone.
For legally required animal procedures, indicate which statutory or business plan schrijven kvk tienen requirements apply with respect to the intended use and market authorisation.
For routine production, describe what will be produced and for which uses. For higher education or training, explain why this project is part of the educational program and describe the learning targets.
Specific drug delivery still faces major problems today. In particular, because of the systemic administration of most drugs, these drugs will reach many organs besides the organ that needs to be treated.
This often leads to many unwanted side-effects in those organs. In addition, delivery of drugs across the cell membrane into the targeted cell is still very inefficient. Therefore, a major advance in drug delivery could be reached by delivering drugs specifically to the diseased cell-type or organ, and at the same time efficiently transporting the drug across the cell membrane 1.
Treatment of these patients often occurs by immunosuppressive drugs, which have a beneficial effect on the kidney, but also result in the shutdown of the systemic immune defense and a reduced resistance to infections.
Therefore, patients with chronic kidney disease would particularly benefit from a specific delivery of effective drugs to the affected part of the kidney.
Obviously, development of drug delivery systems that specifically target other organ- or cell-types could enhance the treatment of many more patients with other organs or cell-type-specific diseases, including patients with alzheimer, rheumatoid arthritis, multiple sclerosis and vascular diseases.
Cell-penetrating peptides CPP form a group of peptides that are amino acids in length that mostly contain several positively charged aminoacids, and have the capability to cross cellular membranes in a non-disruptive way and without apparent toxicity 2.
The uptake mechanism of CPP into the cell can involve both direct translocation and endocytotic-mediated mechanisms, depending on the circumstances 3. CPP can take along cargoes such as small molecule drugs, oligonucleotides, proteins, liposomes and polymeric particles.
These cargoes can either be conjugated by covalent bond formation or by non-covalent complexation. Because of these characteristics, CPP have been considered as a potentially promising drug delivery strategy for many years 4. However, their actual application has been hampered by a lack of information about the exact uptake mechanism of each cell penetrating peptide, about its in vivo distribution, and about its cell- or organ specificity.
Interestingly, a recent study on the bio-distribution of ten different CPP has demonstrated that depending on the number of arginine residues present in the peptide, CPP can show a prominent distribution to either the kidney or the liver 5.
The organ-specific distribution might also be related to their ability to bind specific sugars, including glycosaminoglycans, that are present on the surface of the targeted organ or cell-type 6.
We have previously discovered that a acts as a CPP 7. In a project funded by, Pag. In contrast, other organs including the liver, spleen, skin, brain and heart, exhibited at least a 5-fold lower distribution of the peptide. The distribution of the peptide in the kidney was particularly localized to the, also called the Importantly, these are the main site of inflammation in many chronic kidney diseases.
We found no short-term harmful effect of CPP on mice in our experiments. For nona-arginine, a widely used CPP consisting of nine arginine residues, we did not observe a prominent enrichment in the kidney. All these data fit very nicely with in vitro experiments that showed a much better uptake of CPP in mouse and human and cell lines that originate from in the kidney, compared to other widely-used CPP.
We have now obtained strong evidence that this celspecific activity is associated with a specific receptor present in these cells from the kidney. A manuscript describing these results is currently in preparation for publication. To proceed to an application of CPP in drug delivery, we and others have demonstrated that CPP form nanoparticulate complexes with oligonucleotides, such as sirna, antisense oligonucleotides and mrna 8,9.
In a follow-up project, that is also funded by, we have now shown that CPP enhance the intracellular delivery and activity of antisense oligonucleotides in cell lines. In this way, we were able to effectively suppress the expression of the receptor in activated in vitro.
We could also demonstrate that attachment of to the bio-degradable polymer poly lactic-co-glycolic acid PLGA 10which normally shows a very inefficient cellular uptake, lead to an greatly enhanced uptake of PLGA particles in cell lines. This offers another very interesting possibility, since PLGA particles are FDA approved and can be loaded with small-molecular drugs without the need for covalent coupling.
In conclusion, we have demonstrated that CPP distribute to the of the kidney, and can effectively deliver cargoes such as oligonucleotides and PLGA particles inside these cells. The next important step would be to show that CPP-containing nanoparticles can actually be used in the treatment of kidney diseases, starting with the application in mouse models.
Moreover, our results open the door to look for CPP that target other disease-related cell-types or organs. We have previously found that different membrane components, including sugars, lipids and certain receptors, determine which CPP can enter a certain celtype unpublished results and see also ref.
Since each celtype has its own membrane 'signature', it should be possible to design CPP that target specific celltypes in organs besides the kidney.
In addition, domains linked to celpenetrating activity, for instance stretches of multiple arginines, can be combined with domains that bind specifically to cel- or organ-specific membrane-bound sugars, receptor or other membrane components, which combines celpenetrating activity with celspecificity.
Importantly, for CPP, in vitro assays could predict the in vivo behaviour of the peptide.13 mei Voorbeelden van KPI's in het sales plan zijn het aantal nieuwe klanten, het aantal klantenbezoeken per week, omzetgroei, aantal klachten, verkoop nieuwe producten in de eerste drie maanden, marktaandeel Een periodieke, bv.
maandelijkse, rapportering .
Preparing a Powerful Business Plan Presented by: Greg Garrett and Jim Boyd Illinois Small Business Development Center At Western Illinois University A department of the Illinois Institute of Rural Affairs and Department of Commerce and Economic Opportunity (DCEO) Business Plan Outline.
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