Blocking extracellular activation of myostatin as a strategy for treating muscle wasting.

Many growth factors are intimately bound to the extracellular matrix, with regulated processing and release leading to cellular stimulation. Myostatin and GDF11 are closely related members of the TGFβ family whose activation requires two proteolytic cleavages to release the growth factor from the prodomain. Specific modulation of myostatin and GDF11 activity by targeting growth factor-receptor interactions has traditionally been challenging.

Translating RNA interference into therapies for human disease.

RNA interference (RNAi) represents one of the most promising new frontiers in drug discovery. Breakthroughs in understanding RNA's extensive natural role in essential cellular processes have opened up the potential for a whole new class of drugs based on RNAi. Harnessing the natural process of RNAi, short, double-stranded RNA molecules are able to inhibit expression of genes in a sequence-specific manner.

Cooperative effects of Sonic Hedgehog and NGF on basal forebrain cholinergic neurons.

In ventromedial cells of the developing CNS, Sonic hedgehog (Shh) has been shown to affect precursor proliferation, phenotype determination, and survival. Here we show that Shh and its receptor, Ptc-1, are expressed in the adult rat basal forebrain, and that Ptc-1 is expressed specifically by cholinergic neurons. In basal forebrain cultures, Shh was added alone and in combination with nerve growth factor (NGF), and the number of cholinergic neurons was determined by choline acetyltransferase (ChAT) immunocytochemistry.

Co-grafts of fetal ventral mesencephalon and fibroblasts expressing sonic hedgehog: effect on survival and function of dopamine grafts.

Fibroblasts derived from the Rat2 parental cell line were genetically modified to express the cell-associated form of Sonic hedgehog (Shh) and then co-grafted along with E14 fetal ventral mesencephalon (VM) tissue into the denervated striatum of F344 rats; fetal VM grafts alone or co-grafts using the nonexpressing Rat2 fibroblasts served as controls. Seven weeks after grafting, co-grafts of fetal VM and fibroblasts expressing Shh (Rat2/Shh) contained significantly more tyrosine hydroxylase-positive (TH+) neurons than either the fetal VM grafts or co-grafts of fetal VM plus nonexpressing fibroblasts (Rat2). Despite a significantly higher yield of grafted TH+ neurons in the fetal VM + Rat2/Shh co-grafts than in either of the other two control groups, amphetamine-induced rotational behavior scores were not significantly different between any of the three treatment groups.