Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

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Absence of functional phenylalanine hydroxylase results in phenylketonuria (PKU). Viable treatments remain few, expensive and secondary conditions such as osteopenia occur in most PKU patients. Objective 1: Given the recently described roles of gut microbes to aid host digestion, an orally administered genetically engineered probiotic as the delivery vehicle for enzyme replacement therapy was created. The engineered probiotic, pHENOMMenal, produced phenylalanine ammonia lyase with significant production of trans-cinnamate (phenylalanine cleavage product) in vitro and resulted in a reduction of 515 μM in blood phenylalanine when fed to PKU animals for 14 days (from 2307µM ± 264µM to 1792µM ± 261µM, n = 6, P < 0.05). The control probiotic produced no change in blood phenylalanine. Thus, pHENOMMenal treatment in PKU mice demonstrated engineered microbes could compensate for a metabolic deficiency of the host. Objective 2: Evaluate the PAHenu2 mouse model of PKU for a genetic discrepancy causing ocular enlargement and delayed development observed only after the PAHenu2 mutation was crossed to the C57BL/6J mouse. When compared to healthy littermates, ELISA indicated a consistent but insignificant decrease in plasma IGF-1 and an increase in ocular IGF-1 in PKU animals. SNP screening demonstrated a differential inheritance of IGF-1 alleles in healthy and PKU animals based on PAH allele inheritance. Ocular and developmental phenotypes in the PAHenu2 colony match those described in previous IGF-1 studies. Understanding the IGF-1 inheritance discrepancy will enable better osteopenia research using PAHenu2 mice and allow breeding of a healthier mouse colony for continued research. Collectively the results from this work describe a new therapeutic approach for treatment of PKU as well as a better understanding of the PAHenu2 mouse model to study this disease.

Sabe-se que o hipotireoidismo (Hipo) resulta em supressão do eixo hormônio de crescimento (GH)/ insulin-like growth factor I (IGF-I) e em atraso no desenvolvimento esquelético. Em um estudo anterior, vimos que o tratamento de ratas jovens Hipo com GC-1, um análogo da triiodotironina (T3) seletivo pela isoforma <font face=\"symbol\">b de receptor de hormônio tireoideano (TR<font face=\"symbol\">b), não teve efeito sobre o IGF-I sérico ou sobre a expressão protéica de IGF-I nas lâminas epifisiais, mas parcialmente reverteu alterações esqueléticas decorrentes do Hipo, o que sugere que: (i) o desenvolvimento esquelético requer ações do T3 mediadas pelo TR<font face=\"symbol\">a1 e TR<font face=\"symbol\">b1 (isoformas de TR expressas no osso); ou (ii) requer interações entre o eixo GH/IGF-I e o hormônio tireoideano. Neste estudo, investigamos essas hipóteses tratando ratas recém desmamadas Hipo com T3 ou GC-1 em associação ou não com o GH por 4 semanas. Os nossos achados mostram que o T3 e GH interagem para promover o desenvolvimento ósseo, mas que uma série de efeitos do T3 nesse processo independe do eixo GH/IGF-I e são mediadas pelo TR<font face=\"symbol\">a e/ou TR<font face=\"symbol\">b. / Thyroid hormone (TH) has important effects on bone development and metabolism. It is known that triiodotyronine (T3) has indirect actions in the skeleton through its influence on the production and secretion of growth hormone (GH)/ insulin-like growth factor (IGF-I) and/or other factors. On the other hand, direct actions of T3 on bone are recognized but not yet clear. Most of T3 action is mediaded by its nuclear receptors (TRs). TR<font face=\"symbol\">a1, TR<font face=\"symbol\">b1 e TR<font face=\"symbol\">b2 bind T3, while TR<font face=\"symbol\">a2 does not bind T3 and acts as an antagonist of genic transcription of TR<font face=\"symbol\">a1 and TR<font face=\"symbol\">b1. All these receptors, except TR<font face=\"symbol\">b2, are expressed in chondrocytes of growth plate, osteoblasts and osteoclastos. However, the functional roles of each TR isoformas in the bone development are incompletely understood. A few years, it is development GC-1, a synthetic analog of T3 which is selectivwe for TR<font face=\"symbol\">b1 over TR<font face=\"symbol\">a1. In recent study, we showed that treatment of hypothyroid young rats with T3 revert the IGF-I deficiency and skeleton defects caused by hypothyroidism. Since GC-1 treatment does not effects on serum levels of IGF-I or protein expression of IGF-I in the growth plate, but revert some bone alterations induced by T3 deficiency. Considering the selectivity of GC-1 for TR<font face=\"symbol\">b, these findings suggest that T3 has effects on bone development that are mediated by TR<font face=\"symbol\">b and independent of GH/IGF-I axis. On the other hand, the inability of GC-1 in completely revert the alterations of bone development suggests that the normal skeleton development require (i) T3 actions mediated by TR<font face=\"symbol\">a1 and TR<font face=\"symbol\">b1, or (ii) synergic or additive actions between GH/IGF-I axis and thyroid hormone. To investigate these hypotheses, 21 day-old hypothyroid female rats were treated with T3 or GC-1 in association or not with GH for 4 weeks. Our findings show that T3 interacts with GH to promote body growth, differentiation of growth plate hypertrofic chondrocytes, intramembranous ossification of cranial bone, and increased of bone resistance and other biomechanics parameters that contribute to the best bone quality. On the other hand, ours results suggest strongly that TH acts in bone mass acquisition, in organization of growth plate chondrocytes and endocondral ossification mainly independent of GH/IGF-I axis and via TR<font face=\"symbol\">a and/or TR<font face=\"symbol\">b.

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Made available in DSpace on 2015-07-22T20:50:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-03-30. Added 1 bitstream(s) on 2015-08-11T03:26:08Z : No. of bitstreams: 1 Publico-12662a.pdf: 1757646 bytes, checksum: 6d16ce4a1b202b49620fcd389bf661cb (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:08Z : No. of bitstreams: 2 Publico-12662a.pdf: 1757646 bytes, checksum: 6d16ce4a1b202b49620fcd389bf661cb (MD5) Publico-12662b.pdf: 1556068 bytes, checksum: 9e7692a17342eb563d00b00cb4170335 (MD5) / As evidências científicas que se acumulam ao longo do tempo mostram o impacto positivo do exercício físico para a saúde humana, em especial para a saúde cerebral. Os efeitos como o aumento da atividade neurotrófica do BDNF e do IGF-1, devido ao exercício físico aeróbio, parecem influenciar os neurônios do hipocampo, e estão associados com a melhora do aprendizado e da memória espacial. No entanto, nada se sabe sobre a influência do exercício físico resistido na memória hipocampo-dependente, nem se as vias celulares associadas a essa melhora, pelo exercício físico aeróbio, seriam também ativadas pelo treinamento resistido. Objetivo: Verificar os efeitos dos exercícios físicos aeróbio e resistido na aprendizagem, na memória espacial e nas vias de sinalizações celulares BDNF/ TrKB e do IGF-1/ IGF-1R no hipocampo de ratos. Material e Métodos: ratos Wistar machos adultos foram distribuídos em quatro grupos (controle, CTRL; sham, SHAM; aeróbio, AERO; e resistido, RES), submetidos a oito semanas de treinamento aeróbio (esteira motorizada) ou treinamento resistido (escalada em escada com sobrecarga). Após a intervenção, observou-se que houve, em ambos os grupos AERO e RES, uma melhora da aprendizagem e da memória espacial (hipocampo-dependente), avaliada por meio do labirinto aquático de Morris. Além disto, o grupo AERO ativou mais a via BDNF/ TrKB/ CaMKII do que o RES. No entanto, este grupo ativou mais a via IGF-1/ IGF-1R/ AKT do que o grupo AERO. Apesar de os dois grupos terem aumentado a expressão da sinapsina e da sinaptofisina de forma semelhante. Conclusões: o treinamento aeróbio ou o resistido por oito semanas aumentou, de maneira similar, a aprendizagem e a memória espacial dos ratos. Embora os mecanismos moleculares pelo qual isso ocorreu, até certo ponto tenham sido divergentes. Isso porque, o exercício físico aeróbio ativou a via BDNF/TrKB/CaMKII e, o resistido a via IGF-1/IGF-1R/AKT, embora ambos, de maneira similar, tenham aumentado, no hipocampo, a expressão da sinapsina e da sinaptofisina. / A growing body of scientific evidence indicates that exercise has a positive impact on human health and on neurological health in particular. Effects such as increased BDNF and IGF-1 neurotrophic activity are induced by aerobic exercise and appear to influence hippocampal neurons, leading to improved spatial learning and memory. However, nothing is known about the effect of resistance exercise on hippocampus-dependent memory or whether the cellular pathways associated with aerobic exercise are also activated by resistance training. Objective: we therefore tested whether spatial learning and memory in rats is similarly enhanced by aerobic or resistance exercise and whether the cellular signals involved are similar, focusing on the BDNF/ TrKB and IGF-1/ IGF-1R pathways. Material and Methods: Adult male Wistar rats underwent eight weeks of aerobic training on a treadmill (AERO group) or resistance training on a vertical ladder (RES group); control and sham groups were also included. After the training period, both the AERO and RES groups showed improved learning and spatial memory. In addition, the BDNF/TrkB/CaMKII pathway had a higher activity in the AERO group than in the RES group. In contrast, the RES group showed greater activation of the IGF-1/IGF-1R/AKT pathway. Moreover, the two exercise groups had similar increases in synapsin and synaptophysin expression. Conclusions: We therefore conclude that, in rats, both aerobic and resistance training for eight weeks increases learning and spatial memory in a similar manner. However, the two forms of exercise seem to employ at least partially divergent mechanisms. Specifically, aerobic exercise modulates neuroplasticity selectively via the BDNF/TrkB pathway by activating CaMKII and stimulating the synthesis of synapsin and synaptophysin. In contrast, resistance training appears to increase synapsin and synaptophysin expression via the IGF-1/IGF-1R pathway. / TEDE / BV UNIFESP: Teses e dissertações