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1.
Transfusion ; 49(4): 786-96, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19170985

RESUMO

BACKGROUND: In 2002, the US National Heart, Lung, and Blood Institute (NHLBI) conducted a workshop to determine needs of the cell therapy community. A consensus emerged that improved access to cGMP facilities, regulatory assistance, and training would foster the advancement of cellular therapy. STUDY DESIGN AND METHODS: A 2003 NHLBI request for proposals resulted in four contracts being awarded to three cell-manufacturing facilities (Baylor College of Medicine, University of Minnesota, and University of Pittsburgh) and one administrative center (The EMMES Corporation). As a result, Production Assistance for Cellular Therapies (PACT) was formed. RESULTS: As of October 1, 2008, PACT has received 65 preliminary applications of which 45 have been approved for product manufacture. A variety of cell therapies are represented including T-regulatory cells, natural killer cells, adipose-derived stem cells, cardiac progenitor cells for cardiac disease, hematopoietic progenitor cells (HPCs) for central nervous system applications, cytotoxic T lymphocytes, and dendritic cells. A total of 169 products have been administered under 12 applications and 2 reagents were manufactured and delivered. Fourteen peer-reviewed publications and 15 abstracts have resulted from the PACT project to date. A cell therapy textbook is nearly complete. PACT technical projects have addressed assay development, rapid endotoxin testing, shipping of cell products, and CD34+ HPC isolation from low-volume marrow. Educational Web seminars and on-site training through workshops have been conducted. CONCLUSIONS: PACT is an active and successful cell therapy manufacturing resource in the United States, addressing research and training while forging relationships among academia, industry, and participating institutions.


Assuntos
Bancos de Espécimes Biológicos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Técnicas de Laboratório Clínico , National Heart, Lung, and Blood Institute (U.S.) , Algoritmos , Bancos de Espécimes Biológicos/legislação & jurisprudência , Contratos , Educação Médica Continuada/métodos , Humanos , National Heart, Lung, and Blood Institute (U.S.)/legislação & jurisprudência , Estados Unidos
2.
Biochem Biophys Res Commun ; 357(3): 668-71, 2007 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-17442267

RESUMO

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the leading genetic cause of Parkinson's disease (PD). LRRK2 is predicted to contain kinase and GTPase enzymatic domains, with recent evidence suggesting that the kinase activity of LRRK2 is central to the pathogenic process associated with this protein. The GTPase domain of LRRK2 plays an important role in the regulation of kinase activity. To investigate how the GTPase domain might be related to disease, we examined the GTP binding and hydrolysis properties of wild type and a mutant form of LRRK2. We show that LRRK2 immunoprecipitated from cells has a detectable GTPase activity that is disrupted by a familial mutation associated with PD located within the GTPase domain, R1441C.


Assuntos
Guanosina Trifosfato/metabolismo , Mutação , Proteínas Serina-Treonina Quinases/metabolismo , Substituição de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Guanosina Difosfato/metabolismo , Humanos , Hidrólise , Immunoblotting , Imunoprecipitação , Cinética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética
3.
J Neurochem ; 102(1): 93-102, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17394548

RESUMO

Several mutations have been found in the leucine-rich repeat kinase 2 gene (LRRK2), encoding the protein dardarin, which are associated with autosomal dominant Parkinson disease. We have previously shown that mutant LRRK2/dardarin is toxic to neurons and neuron-like cell lines in culture and that some mutations are also associated with an inclusion-body phenotype. There is a homologous kinase, LRRK1, which has a similar domain structure but is not known to carry mutations causing Parkinson disease. In the current study, we introduced mutations at equivalent residues in both LRRK2 and LRRK1 to determine their effects in cells. We show that mutations in dardarin are more prone to form inclusion bodies in transfected cells and are more toxic than equivalent mutations in LRRK1. This work suggests that dardarin/LRRK2 is inherently more damaging than LRRK1.


Assuntos
Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Western Blotting , Encéfalo/enzimologia , Células COS , Células Cultivadas , Chlorocebus aethiops , Clonagem Molecular , Citosol/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Imunoprecipitação , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Microscopia Confocal , Mutação/fisiologia , Fosfoproteínas/metabolismo , Fosforilação , Plasmídeos/genética , Proteínas Serina-Treonina Quinases/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
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