Biochemistry and Molecular Biophysics Graduate Group

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pixelBiomedical Imaging and Supramolecular Assemblies

Ben E. Black, Ph.D.

Chromosome segregation; chromatin structure; epigenetic centromere specification; hydrogen/deuterium exchange

Associate Professor of Biochemistry & Biophysics
913A Stellar-Chance Labs
Tel: 215-898-5039 (office) / Fax: 215-573-7058
Lab: 912 Stellar Chance Labs
Tel: 215-898-4476 (lab)
Email: blackbe@mail.med.upenn.edu

Dr. Black's laboratory is interested in how particular proteins direct accurate chromosome segregation at mitosis. In humans, the chromosomal element—the centromere—that directs this process is not defined by a particular DNA sequence. Rather, the location of the centromere is dictated by an epigenetic mark generated by one or more resident proteins. These centromeric proteins interact directly with the DNA to create a specialized chromatin compartment that is distinct from any other part of the chromosome. By taking biophysical, biochemical, and cell biological approaches, our work is to define the composition and physical characteristics of the protein and protein/DNA complexes that epigenetically mark the location of the centromere on the chromosome. This work involves building centromeric chromatin from its component parts for analysis of its physical characteristics, developing biochemical assays to reconstitute steps in the process of establishing and maintaining the epigenetic mark, and using cell-based approaches to study the behavior of proteins involved in centromere inheritance and function.
For the physical studies of centromeric chromatin, one emerging technique that has already proven extremely useful is hydrogen/deuterium exchange coupled with mass spectrometry to assess conformational flexibility of centromeric proteins. Hydrogen/ deuterium exchange along the polypeptide backbone occurs at rates that can span a huge dynamic range, and this experimental approach has been applied by many laboratories to diverse problems in protein chemistry [including several ongoing efforts at UPenn]. These include global questions of protein folding, as well as more protein-specific questions of conformational alterations upon assembly into higher-order structures or upon changing states in the case of "molecular switches". We are interested in extending this technique to assess the properties conferred by the incorporation of centromeric proteins into higher-order chromatin structure, as well as to the study of proteins involved in other steps of regulating chromosome segregation.

 

Theresa M. Busch, Ph.D.

Photodynamic therapy, tumor microenvironment

Research Associate Professor of Radiation Oncology
8-126 Smilow Center for Translational Research
Tel: 215-573-3168 / Fax:215-898-0090
Email: buschtm@mail.med.upenn.edu

Our primary research focus is the investigation of photodynamic therapy (PDT) for the treatment of solid malignancies. In PDT, diseased tissue is illuminated by specific wavelengths of visible light after the delivery of a photosensitizer to that tissue. The light-excited photosensitizer interacts with oxygen to produce reactive oxygen species that damage the tissue and its associated stroma, including the supporting vascular network.

Our research centers on the study of biophysical limitations of treatment response to PDT. This includes the study of heterogeneities in the distributions of oxygen, photosensitizing drug, and light. Our studies have found that PDT can create widespread, severe hypoxia during illumination, even in tumor cells immediately adjacent to perfused blood vessels. Furthermore, noninvasive monitoring has shown PDT effect on tumor oxygenation and blood flow during the illumination period to be predictive of an animal’s long-term response to therapy. Such findings are extremely relevant to clinical PDT applications, where significant heterogeneity in hypoxia and photosensitizer distributions among the tumors of PDT patients will contribute to variable therapeutic outcomes. Indeed, we have documented a relationship between biochemical (PSA) response to PDT in prostate cancer patients and levels of photosensitizer drug and light energy in their prostates. Ultimately, in order to improve the clinical therapeutic index and efficacy of PDT, we aim to alter the microenvironment of tumors undergoing treatment as guided by noninvasive monitoring of their response.

 

Michael A. Lampson, Ph.D.

Chromosome segregation in mitosis and meiosis, biosensors for mitotic kinases

Assistant Professor of Biology
204-I Carolyn Lynch Laboratory
433 South University Ave.
Philadelphia, PA 19104
Tel: 215-746-3040
Email: lampson@sas.upenn.edu

Our research addresses molecular mechanisms that maintain genomic integrity during cell division. The replicated chromosomes are physically segregated at each division to create two genetically identical daughter cells.  Segregation errors lead to loss or gain of whole chromosomes in the daughter cells, or aneuploidy, which is strongly associated with human cancer, developmental disease, and infertility.  A complex and highly dynamic cellular machinery ensures accurate chromosome segregation. While many of the key components have been identified, we now face the challenge of understanding how the system is controlled. Using high-resolution light microscopy, combined with molecular perturbations introduced by RNAi or with small molecule inhibitors, we are examining key processes in cell division in real time in living cells. Research in the lab is currently focused in two directions, as detailed below.

First, mitotic kinases and phosphatases are critical for the regulation of cell division, and we are developing probes based on fluorescence resonance energy transfer (FRET) to examine signaling networks at specific intracellular structures in living cells. A core project in the lab is to examine signaling at the centromere, the site on each chromosome that attaches to the mitotic spindle.  Accurate chromosome segregation requires that each replicated chromosome pair attaches to spindle microtubules in the correct configuration, so that sister chromosomes are pulled in opposite directions at anaphase. Attachment errors must be (1) detected, to activate the spindle checkpoint, and (2) corrected before anaphase onset. Both processes depend on signaling at individual centromeres. We showed how the mitotic kinase Aurora B acts as a tension sensor to regulate microtubule interactions (Liu et al. 2009). Building on these findings, we are developing models for site-specific signaling networks, involving both kinases and phosphatases, that control cell division.

Second, we are addressing the question of why female fertility decreases with age. The best evidence to date is that the decreased fertility is due to an increase in the production of aneuploid eggs by older females (both human and mouse), which clearly points to chromosome segregation defects as an underlying cause. We are using mouse oocytes as a model system to understand the defects leading to aneuploidy. Our goal is to focus on basic molecular mechanisms involved in meiotic chromosome segregation, such as the spindle checkpoint, kinetochore function, and cohesion, but the relevance for reproductive health is obvious. This project provides an opportunity to study cell division in a system that has clear importance for human health, the mammalian oocyte, but that has received relatively little attention compared to some other model systems. We will address both the age-associated increase in aneuploidy, which is currently quite mysterious, and basic mechanisms of meiosis

 

Zhe Lu, M.D., Ph.D.

Structure-function relationship of ion channels; molecular mechanisms of protein-protein interactions

Professor of Physiology
728 Clinical Research Building
Tel: 215-573-7711 / Fax: 215-573-1940
Email: zhelu@mail.med.upenn.edu
Lu Physiology website

Dr. Lu's laboratory investigates the molecular and the biophysical mechanisms of inward-rectifier potassium channels and cyclic-nucleotide-gated channels, using a combined approach of biophysics, biochemistry and molecular biology. Specifically, they investigate the channel mechanisms that enable the inward-rectifier potassium channels to control cardiac pacemaker rate, to regulate communication strength between neurons and to couple blood glucose level to insulin secretion, and the mechanisms that enable the cGMP-gated channel to mediate visual photo-transduction in the eye. Additionally, they develop specific inhibitors for various types of physiological and pathophysiological important ion channels through both passive screening and active design.

 

E. Michael Ostap, Ph.D.

Biochemistry of contractile proteins, biophysics of cell motility, and characterization of unconventional myosins

Professor of Physiology
Director, Pennsylvania Muscle Institute
700A Clinical Research Building
Tel: 215-573-9758 (office); 215-898-3685 (lab) / Fax: 215-573-1171
Email: ostap@mail.med.upenn.edu
Ostap Laboratory Page

The goal of our research is to understand the function, regulation, and molecular mechanism of the ubiquitously expressed molecular motors called myosins. The physiological roles and molecular mechanisms of many members of the myosin superfamily are not well understood. To better define the roles of myosin isoforms, we are using a rigorous interdisciplinary approach that combines chemistry, biophysics, cell, and molecular biology. We are obtaining a physical framework in which to discuss the cellular functions of myosins by investigating the enzymatic and structural properties of native and recombinant myosin isoforms, and we are investigating the in vivo localization, organization, dynamics, and physiology of myosin-I in fixed and live cells using high-resolution microscopy techniques.

 

Ravinder Reddy, Ph.D.

Sodium and oxygen-17 MR methods; multiple quantum and polarization transfer MR techniques

Professor of Radiology
Director, Center for Magnetic Resonance and Optical Imaging
B1-Stellar-Chance Labs
Tel: 215-898-5708 / Fax: 215-573-2113
Email: krr@mail.med.upenn.edu
MMRRCC Homepage

My research interests are in developing novel, multinuclear (²³Na, ¹?O, ¹³C and ¹H) magnetic resonance imaging and spectroscopic techniques for early diagnosis and quantification of physiological and functional parameters in pathologies such as arthritis, stroke, cancer and Alzheimer’s Disease. Our pulse sequence developmental approaches exploit quadrupolar spin-dynamics, polarization transfer, multiple quantum coherences, indirect detection and spin locking for studying molecular dynamics in biological tissues in vivo. In particular, sodium and spin-locking MRI are targeting to map proteoglycan molecules (e.g. Aggrecan) in the connective tissues in vivo. Indirect ¹?O MRI is aimed at studying cerebral blood flow and cerebral oxidative metabolism and tumor perfusion and metabolism. Spin-locking MRI is being developed to impart novel contrast in various tissue types (brain, connective tissues and tumors), macromolecular ordering in tissues, and visualize and quantify Amyloidal plaques in Alzheimer’s disease in vivo

 

Phong Tran, Ph.D.

Cytoskeleton organization and cellular pattern formation

Associate Professor of Cell & Developmental Biology
1009 Biomedical Research Building II/III
Tel: 215-746-2755 / Fax: 215-898-9871
Email: tranp@mail.med.upenn.edu
Tran Cell and Developmental Biology Homepage

The Tran lab is interested in understanding how positional information is generated within the cell by the cytoskeleton. For example, their previous studies in fission yeast have shown that bundles of microtubules can set up a spatial map for the cell to know where to grow and where to position its nucleus.

Microtubule architecture and dynamics are influenced by both plus- and minus-end microtubule-associated-proteins. A long-term goal, then, is to understand what role these proteins play in the establishment and maintenance of cellular spatial domains by microtubules. The Tran lab plans to: 1) identify the molecular components of the microtubule organizing centers, 2) define the interactions of known microtubule-associated-proteins with the microtubule ends and the roles of these proteins in bringing about proper nuclear positioning and cellular pattern, and 3) develop and apply advanced optical imaging and analysis methods to the yeast system.

High resolution optical imaging and analysis techniques, use of the green fluorescent protein and its variants as non-invasive fluorescent biosensors, and the model organism Schizosaccharomyces pombe with its well-defined shape, size, and genetic tractability constitute ideal, proven tools for studying cellular spatial organization and regulation.

 

Andrew Tsourkas Ph.D.

Molecular imaging, drug delivery, nanotechnology, and biotherapeutics

Associate Professor of Bioengineering
110 Hayden Hall
Tel: 215-898-8167
Email: atsourk@seas.upenn.edu
http://www.seas.upenn.edu/~atsourk/

The rapid advancement in our understanding of the regulatory and signaling pathways responsible for cell growth, differentiation, and death has led to the identification of an array of anomalies in the genome and proteome that can be associated with disease. Our laboratory is interested in developing molecular imaging probes that target these anomalies to locate and study diseased states in vivo. We are developing probes that target a wide range of biological processes including gene regulation, mRNA localization, protein expression, and enzymatic activity. Multiple imaging platforms are used including magnetic resonance, fluorescence, and bioluminescence and applications range from studying the complex intracellular dynamics of individual cells to the early detection of disease in a clinical setting.

 

Sergei A. Vinogradov, Ph.D.

Functional macromolecules, optical imaging probes, porphyrin chemistry, dendrimer chemistry, oxygen microscopy and tomography

Associate Professor of Biochemistry & Biophysics
1013B Stellar-Chance Labs
Tel: 215-573-7524
Email: vinograd@mail.med.upenn.edu

Our research revolves around functional molecular systems related to biological objects by function or by application. We use methods of synthetic organic chemistry to rationally design and construct molecules with preferred degree of active site encapsulation, predefined photophysical properties and tunable energy and electron transfer pathways. Our special area of interest is development of advanced probes for optical microscopy and imaging. In particular, we are developing methods for optical imaging of oxygen in biological tissues using phosphorescence quenching. We design and use dendritically protected phosphorescent probes in combination with instrumentation and algorithms developed in our laboratory to perform in vivo oxygen imaging experiments, addressing various biological problems through collaborations with scientists from Penn Medical School and other universities.

Two areas of organic chemistry are recurrent in our research: porphyrins and dendrimers. We study a new class of near-infrared absorbing p-extended porphyrins (tetrabenzoporphyrins, tetranaphthaloporphyrins etc), for which we have devised a practical synthetic approach. We look into the photophysics, including non-linear optical properties, acid/base properties and electrochemistry of these new porphyrins, addressing various structure-property relationships in the extended porphyrin family.

Dendrimers provide a convenient and straightforward way for macromolecular encapsulation of optically active sites. Dendritic cages control access of small molecules to the encapsulated cores, providing an effective way of selective sensing of small molecules in biological systems. Dendrimers with porphyrin cores also bear many similarities with heme containing proteins. We use photophysical methods to probe diffusion of small molecules inside dendrimers, serving as models of natural macromolecular scaffolds.
Currently, we are currently developing two new technologies for biological oxygen imaging: oxygen tomography by phosphorescence lifetime and multiphoton microscopy of oxygen. Both techniques are relevant to research in cancer and peripheral vascular disease, while oxygen microscopy is also expected to have an impact in ophthalmology and neuroscience. Optical probes for oxygen tomography and microscopy, theory, algorithms and instrumentation are being addressed in our group.

 

Felix W. Wehrli, Ph.D.

MRI of biomaterials microstructure, mathematical modeling, image processing

Professor of Radiology, and Biochemistry & Biophysics
1 Founders Pavilion
Tel: 215-662-7951 / Fax: 215-662-7263
Email: wehrlif@uphs.upenn.edu
LSNI Website

Research of the Laboratory is aimed at quantitatively characterizing tissue microarchitecture and its relationship to physiology and function by means of spatially resolved nuclear magnetic resonance in animals and humans. The current focus of the Laboratory is on the development of new methods for the quantitative assessment of metabolic bone disease by means of the MR-based "virtual bone biopsy", and new methods for the study of bone matrix and mineral micro- and nanostructure. A second line of research focuses the development of MRI-based methods for noninvasive measurement of blood oxygen saturation Additional projects deal with ultrahigh-resolution microscopy of neuronal architecture in spinal cord injury models as well as methods for indirect assessment of tissue microstructure by means of diffusion diffraction and multiple quantum coherence imaging.

 

John W. Weisel, Ph.D.

Structural studies of molecular/cellular mechanisms in blood clotting and fibrinolysis

Professor of Cell & Developmental Biology
1154 Biomedical Research Building II/III
Tel.: 215-898-3573 / Fax: 215-898-9871
Email: weisel@mail.med.upenn.edu
Weisel Cell and Developmental Biology Web page

The research in this lab has focused on the molecular and cellular mechanisms of blood coagulation and fibrinolysis, as analyzed through the use of various biophysical and structural techniques, including visualization of molecules and supramolecular aggregates and measurements of mechanical properties of cellular and extracellular structures. Molecular mechanisms of the dissolution of the clot by the fibrinolytic system are under investigation. The interactions of integrins with various adhesive proteins and with the cytoskeleton is also a focus of research. The results of these studies have implications for basic mechanisms of protein-protein and protein-cell interactions as well as for clinical aspects of hemostasis, thrombosis and atherosclerosis.