Gustavo Kunde Rohde, Assistant Professor, Biomedical Engineering, Carnegie Mellon University

Monday, May 16, 2011
2:00 PM – 3:00 PM
Beckman Institute Auditorium

Novel biomedical imaging techniques have enabled the acquisition of quantitative information from cells, tissues, and organs with unprecedented accuracy and specificity. Combined with the availability of vast computational resources, quantitative biomedical imaging pipelines have the potential to accelerate scientific discovery and improve clinical practice. An important engineering problem in this area relates to extracting quantitative information related to the form (shape and texture) of cells, tissues, and organs. I will describe our recent efforts toward the development of a general purpose segmentation method and present preliminary evidence that a tool capable of high-enough accuracy for quantitative imaging pipelines may one day be available. In addition, recent efforts in developing geometric data analysis tools for mining morphological information from biomedical image data will be described. In particular, I will describe the application of deformation and transportation related metrics, in combination with discriminant analysis techniques, towards understanding the distribution of cellular patterns in cancerous and normal tissues.

“High resolution mapping of Twist to DNA in Drosophila embryos: Efficient functional analysis and evolutionary conservation” was published in the Genome Research Journal, Advanced Online Access, March 2011. Genome Research focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine.

From the abstract:

“Cis-regulatory modules (CRMs) function by binding sequence specific transcription factors, but the relationship between in vivo physical binding and the regulatory capacity of factor-bound DNA elements remains uncertain. We investigate this relationship for the well-studied Twist factor in Drosophila melanogaster embryos by analyzing genome-wide factor occupancy and testing the functional significance of Twist occupied regions and motifs within regions … Our results show that high resolution in vivo occupancy data can be used to drive efficient discovery and dissection of global and local cis-regulatory logic.” (more)

CACR staff member Shirley Pepke analyzed the ChIP-seq binding data and found enhanced evolutionary conservation associated with candidate cis regulatory modules.

About Cellcenter: The goal of the Center for Integrative Study of Cell Regulation (Cell Center) is to develop new computational methods for understanding how the many genes and proteins that make up individual cells work together to carry out specialized functions of different cell types, including neurons, plant cells, and bacteria. See www.cellcenter.caltech.edu for further information.

Read more in the Caltech Press Release

“Models of interactions of Ca(2+), CaM, and monomeric catalytic subunits of CaMKII: a piece of the post-synaptic signaling network puzzle”
Dr. Shirley Pepke, Caltech Center for Advanced Computing Research

Calcium (Ca) signal transduction is a fundamental driver of synaptic plasticity in neurons. The molecule Calmodulin (CaM) is an important second messenger in Ca signaling in the post-synaptic density, integrating Ca levels via four binding sites. CaM transmits Ca signal information downstream through selective binding to target enzymes such as calmodulin-activated kinase II (CaMKII). Prior models of Ca/CaM/CaMKII have focused on the role of the unique holoenzyme structure of CaMKII in generating sensitivity and selectivity in response to dynamic Ca input. I will present models of Ca/CaM/CaMKII binding and phosphorylation reactions (developed within the Kennedy lab) that incorporate detailed representations of Ca/CaM and Ca/CaM/CaMKII binding states and explore the resulting impact on phosphorylation rates of monomeric catalytic subunits of CaMKII. Ca/CaM state models are seen to be necessary to accurately predict CaMKII phosphorylation levels under the low Ca conditions that are typical in neurons. Additionally, specific kinetic rate ranges in the models are shown to confer frequency sensitivity independent of a CaMKII holoenzyme structure. Sensitivity analysis on the estimated model parameters confirm these findings across sampled ranges of all parameters and point to areas where further experiments are necessary to establish quantitative values. While the results presented will be for numerical integration of an ODE representation of the reaction network, the models are easily implemented within a stochastic simulation framework that allows analysis of the response to Ca inputs with low molecule numbers as well as gradients in both time and space. The models promise new insight into the relative roles of thermodynamics, kinetics, molecular structure, and spatial distributions of signaling proteins in determining the synaptic response to Ca influxes.