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Palo Alto, CA, United States

Webster M.J.,Stanley Medical Research Institute | Elashoff M.,CardioDx | Weickert C.S.,University of New South Wales
International Journal of Developmental Neuroscience | Year: 2011

Theories concerning the pathology of human neurodevelopmental disorders that emerge in adolescence, such as schizophrenia, often hypothesize that there may be a failure of normal cortical synaptic loss or pruning. However, direct evidence that synaptic regression is a major developmental event in the adolescent human cortex is limited. Furthermore, developmental work in rodents suggested that synaptic regression in adolescence is not a major feature of cortical development. Thus, we set out to determine when and to what extent molecular markers of synaptic terminals [synaptophysin (SYP), SNAP-25, syntaxin1A (STX1A), and vesicle-associated membrane protein 1 (VAMP1)] are reduced during postnatal human life spanning from 1 month to 45 years (n=69) using several different quantitative methods, microarray, qPCR and immunoblotting. We found little evidence for a consistent decrease in synaptic-related molecular markers at any time point, but instead found clear patterns of gradual increases in expression of some presynaptic markers with postnatal age (including SNAP-25, VAMP1 and complexin 1 (CPLX1) mRNAs and 6/6 presynaptic proteins evaluated). A measure of synaptic plasticity [growth-associated protein of 43. kDa (GAP-43)] was elevated in neonates, and continued robust expression throughout life. Since CPLX1 protein is enriched in inhibitory terminals we also tested if the protein product of complexin 2 (CPLX2), which is enriched in excitatory neurons, is more specifically reduced in development. In contrast to CPLX1, which showed a steady increase in both mRNA and protein levels during postnatal development (both r> 0.58, p< 0.001), CPLX2 mRNA decreased from infants to toddlers (r=-0.56, p<0.001), while CPLX2 protein showed a steady increase until young adulthood (r=0.55, p<0.001). Furthermore, we found that indices of the dendrites [microtubule associated protein 2 (MAP2)] and spines (spinophilin and postsynaptic density protein of 95. kDa (PSD95)] showed some evidence of reduction over time at the mRNA level but the opposite pattern, of a developmental increase, was found for PSD95 and spinophilin protein levels. Taken together, the postnatal changes in molecular components of synapses supports the notion that growth and strengthening of synaptic elements is a major developmental event occurring in the frontal cortex throughout childhood and that maintenance of steady state levels of synapse-associated molecules may predominate during human adolescence. © 2010 ISDN. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 205.80K | Year: 2014

DESCRIPTION (provided by applicant): Current tube-based methods for collecting whole blood RNA such as PAXgeneTM have a number of limitations including need for access to phlebotomy, temperature controlled transport, and relatively large volumes of whole blood. No solid-matrix based methods for obtaining RNA from whole blood currently exist. Our goal is the development and implementation of a solid, matrix-based approach for obtaining and stabilizing both RNA and DNA from whole blood, which would address these limitations. In conjunction with investigators at General Electric, we have prototyped an initial platform, term RNA Stabilization Matrix (RSM). In the current proposal we plan to expand upon our initial work in four areas: (1) We plan to develop automated methods using liquid handling robotics for extracting RNA from RSM; such methods will increase throughput as well as decrease variability associated with manual processing. (2) We plan to develop methods allowing for whole transcriptome analysi


Patent
CardioDx | Date: 2012-08-24

Peripheral blood markers are provided whose expression levels correlate with smoking status. Predictive models developed using highly informative markers are disclosed, along with systems, kits, and methods for using the markers to provide a biochemical surrogate for a subjects smoking status. In some embodiments, the smoking-related disease is chronic obstructive pulmonary disease, chronic bronchitis, emphysema, lung cancer, and/or asthma.


Patent
CardioDx | Date: 2014-01-16

Markers and methods useful for assessing coronary artery disease in a subject are provided, along with kits for measuring their expression. Also provided are predictive models, based on the markers, as well as computer systems, and software embodiments of the models for scoring and optionally classifying samples.


Patent
CardioDx | Date: 2015-07-17

Markers and methods useful for assessing coronary artery disease in a subject are provided, along with kits for measuring their expression. Also provided are predictive models, based on the markers, as well as computer systems, and software embodiments of the models for scoring and optionally classifying samples.

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