Th1 cytokines are upregulated by adenoviral vectors in the brains of primed mice.

A major disadvantage of first generation adenoviral vectors for gene therapy in the brain is the immune response they elicit. Human adenovirus is a common respiratory virus and earlier exposure to it has important implications for gene therapy. We show that the immune response against E1-deleted adenoviral vectors in the brain is more deleterious in animals previously exposed to the virus.

Readministration of adenoviral gene delivery to dopamine neurons.

An approach currently being explored as treatment for Parkinson's disease is gene therapy. An important question concerns the duration of transgene expression in dopamine neurons and the issues of vector persistence, neuronal damage and the feasibility of readministering vector to the same neuronal population. We show, using an adenoviral vector expressing the LacZ reporter gene, that transgene expression declined over time but with minimal loss of dopamine neurons or vector DNA.

Hypogonadal mouse, a model to study the effects of the endogenous lack of gonadotropins on apoptosis.

Testicular apoptosis is involved in the regulation of germ cell numbers, allowing optimal sperm production. Apoptosis has been described to occur in response to the absence of hormonal stimulation of the testis. Here we investigate the effect of the physiological lack of gonadotropins from birth using the hypogonadal (homozygous for the mutant allele Gnrh1(hpg)) mouse as a model.

Neuropathological consequences of delivering an adenoviral vector in the rat brain.

Background: Adenoviruses have many advantages as vehicles for gene delivery to the central nervous system (CNS) and retrograde transport of vectors to axonally linked sites has been postulated as a method for targeting neurons in remote brain regions. To investigate optimisation of this we injected different doses of vector and have documented the neuropathological side effects.

Methods: Increasing doses of a first-generation adenoviral vector, expressing the lacZ gene, were inoculated in the rat striatum and beta-galactosidase expression was examined at the primary and secondary sites.

Influence of mutations affecting gonadotropin production or responsiveness on expression of inhibin subunit mRNA and protein in the mouse ovary.

Measurement of inhibins A and B in the serum of normal cyclic rodents has implicated FSH in the regulation of these peptides within the ovary. To extend these observations we have used a panel of mutant mice carrying mutations which affect either the production of, or the ability to respond to, FSH and LH. As a consequence, the females are infertile and show different degrees of follicular development.

Regulation of Sertoli cell number and activity by follicle-stimulating hormone and androgen during postnatal development in the mouse.

The roles of FSH and androgen in the postnatal development of Sertoli cell number and function have been investigated using mice that lack FSH (FSHbetaKO), FSH-receptors (FSHRKO), or androgen receptors (Tfm). At birth and d 5, Sertoli cell number was normal in FSHRKO and FSHbetaKO mice, but was significantly reduced on d 20 and in adulthood. In contrast, Sertoli cell number was reduced at birth in Tfm mice and remained significantly less than normal up to adulthood.

Failure of normal Leydig cell development in follicle-stimulating hormone (FSH) receptor-deficient mice, but not FSHbeta-deficient mice: role for constitutive FSH receptor activity.

Previous studies have suggested that FSH may be involved in regulation of Leydig cell function. We have examined this directly using two mouse models with null mutations in either the FSH beta-subunit (FSHbetaKO mice) or the FSH receptor (FSHRKO mice). Circulating LH levels were normal in adult FSHbetaKO mice, but were significantly increased in FSHRKO mice.

Reversible infertility in male mice after oral administration of alkylated imino sugars: a nonhormonal approach to male contraception.

During mammalian spermatogenesis, male germ cells undergo a dramatic transformation, which includes a change of shape, nuclear condensation, and development of specialised structures, such as an acrosome, and a flagellum with a mitochondrial sheath. We have found a previously undescribed pharmacological approach to intervene in these events. After oral administration of the alkylated imino sugar N-butyldeoxynojirimycin (NB-DNJ) to mice, epididymal spermatozoa displayed a spectrum of abnormal head shapes, and acrosomal antigens were mostly absent or displayed irregular patterns.