Biomedical subjects

Shelley J Allen

Publications and source records attributed to Shelley J Allen.

5 recordsLinked to original sources

PubMed2005

TrkAd5: A novel therapeutic agent for treatment of inflammatory pain and asthma.

Elevated levels of nerve growth factor have been linked to the onset and persistence of many pain-related disorders and asthma. Described here are the design, expression, refolding, and purification of a monomeric (nonstrand-swapped) form of the binding domain of the nerve growth factor receptor, designated TrkAd5. We have shown that TrkAd5 produced recombinantly binds nerve growth factor with picomolar affinity. TrkAd5 has been characterized using a variety of biophysical and biochemical assays and is shown here to be stable in both plasma and urine. The palliative effects of TrkAd5 are demonstrated in animal models of inflammatory pain and allergic asthma. We conclude that TrkAd5 will prove effective in ameliorating both acute and chronic conditions where nerve growth factor acts as a mediator and suggest a role for its application in vivo as a novel therapeutic.

Amino Acid Sequence↗

PubMed2005

Premorbid effects of APOE on synaptic proteins in human temporal neocortex.

APOE affects the risk of Alzheimer's disease (AD) and course of several other neurologic diseases. Experimental studies suggest that APOE influences synaptogenesis. We measured the concentration of two presynaptic proteins, synaptophysin and syntaxin 1, and also postsynaptic density-95 (PSD95), in superior temporal cortex from 42 AD and 160 normal brains, and determined the APOE genotypes. The concentration of both presynaptic proteins was approximately two-thirds lower in AD than normal brains and that of PSD95 one-third lower. No effect of APOE on synaptic proteins was found in advanced AD. However, in normal brain, epsilon4 was associated with lower concentrations of all three synaptic proteins and epsilon2 with significantly elevated PSD95 (p=0.03). A combined measure of synaptic proteins showed a significant linear decrease from epsilon2 through epsilon3 to varepsilon4 (p=0.01). APOE influences the concentration of synaptic proteins in normal superior temporal cortex and may thereby affect the response to injury, and the risk and outcome of a range of neurologic diseases.

Adult↗

PubMed2005

Decrease in bladder overactivity with REN1820 in rats with cyclophosphamide induced cystitis.

PURPOSE: Studies suggest that nerve growth factor (NGF) contributes to bladder overactivity stemming from bladder inflammation. Studies were performed to determine the NGF dependence of cyclophosphamide (CYP) induced changes in bladder function using the recombinant NGF sequestering protein REN1820. MATERIALS AND METHODS: Urodynamic testing and behavioral observations were made in female rats treated with CYP (4 or 48 hours) and REN1820 or vehicle. RESULTS: Rats examined 4 or 48 hours after CYP treatment plus REN1820 showed significantly fewer nonvoiding contractions with smaller amplitude (p </=0.01). Rats examined 48 hours after CYP treatment plus REN1820 showed decreased voiding frequency (p </=0.01). No changes in filling, threshold or micturition pressure were observed with REN1820 treatment. Rats treated with CYP plus REN1820 showed greater mobility and normal resting postures compared with rats treated with CYP plus vehicle. CONCLUSIONS: These studies demonstrate that the use of the NGF sequestering protein REN1820 in rats with CYP induced cystitis decreases bladder overactivity. This is characterized by 1) a decrease in the number and amplitude of nonvoiding contractions and 2) decreased voiding frequency. Rats treated with REN1820 showed greater mobility and normal resting postures, which may reflect improved overall health or well-being. REN1820 may prove to be a novel therapeutic in individuals with the chronic inflammatory bladder syndrome interstitial cystitis.

Animals↗

PubMed2002

alpha- and beta-secretase: profound changes in Alzheimer's disease.

The amyloid plaque, a neuropathological hallmark of Alzheimer's disease, is produced by the deposition of beta-amyloid (Abeta) peptide, which is cleaved from Amyloid Precursor Protein (APP) by the enzyme beta-secretase. Only small amounts of Abeta form in normal brain; more typically this is precluded by the processing of APP by alpha-secretase. Here, we describe a decrease in alpha-secretase (81% of normal) and a large increase in beta-secretase activity (185%) in sporadic Alzheimer's disease temporal cortex. Since alpha-secretase is present principally in neurons known to be vulnerable in Alzheimer's disease, and there is known competition between alpha- and beta-secretase for the substrate APP, it is significant that the majority of Alzheimer samples tested here were low in alpha-secretase. Eighty percent of Alzheimer brains examined had an increase in beta-secretase, a decrease in alpha-secretase, or both; which may account for the means by which the majority of people develop Alzheimer's disease.

Aged↗

PubMed2002

A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4.

TrkB is a member of the Trk family of tyrosine kinase receptors. In vivo, the extracellular region of TrkB is known to bind, with high affinity, the neurotrophin protein brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4). We describe the expression and purification of the second Ig-like domain of human TrkB (TrkBIg(2)) and show, using surface plasmon resonance, that this domain is sufficient to bind BDNF and NT-4 with subnanomolar affinity. BDNF and NT-4 may have therapeutic implications for a variety of neurodegenerative diseases. The specificity of binding of the neurotrophins to their receptor TrkB is therefore of interest. We examine the specificity of TrkBIg(2) for all the neurotrophins, and use our molecular model of the BDNF-TrkBIg(2) complex to examine the residues involved in binding. It is hoped that the understanding of specific interactions will allow design of small molecule neurotrophin mimetics.

Amino Acid Sequence↗