CELLS TO SYSTEMS

This course will provide a foundation in cell biology, structure and function. Topics include cytoskeleton, cell adhesion, basic membrane transport processes, the ionic basis of membrane excitability, various types of ion channels, the process and role of endocytosis in cell function. Students will learn the principles of intracellular signaling including the individual components of intracellular signaling pathways from receptor-ligand interactions to modulators to second messengers to effectors as well as signaling events associated with cell cycle, cell growth (cancer), cell senescence and cell death (apoptosis). Students will be introduced to genetic methodologies used to manipulate, interpret and define gene function. The final portion of the semester will cover selected topics designed to integrate basic molecular and cellular biology concepts in a discussion of complex biological systems operating in intact organism.

Cytoskeleton

• This lecture begins with an overview of the functions of the cytoskeleton, and the three major polymeric filaments that comprise the cytoskeleton in eukaryotic cells. The lecture then focuses on microtubules and how their assembly is regulated.

Microtubules

• This lecture continues with microtubules, and focuses on their interactions with molecular motor proteins as well as the mechanisms by which microtubules are organized in cells.

Actin/Myosin

• This lecture focuses on the functions of actin filaments in living cells, and the mechanisms by which they are regulated and organized. A number of different actin regulatory proteins are discussed, with a particular emphasis on the myosin family of molecular motors that impose forces on actin filaments.

Cell Motility/Cell Polarity

• This lecture utilizes information from the previous four lectures to provide a detailed view of how cells locomote through their environment.

Cell Adhesion

• This lecture focuses on the various types of cell junctions and modes for adhesion of cells to other cells and substrates. Topics include embryogenesis, immune cell chemotaxis, tumor cell metastasis, as well as the types of adhesion molecules involved in these processes and events.

Mitochondria

• This lecture deals with the variety of critical roles played by mitochondria in cellular physiology. Evolutionary origins of mitochondria and the vast divergence of mitochondrial functions in different eukaryotic lineage are discussed. In addition to the energy generation, the importance of mitochondria in regulating calcium levels in the cell as well the triggering of the apoptotic pathway is described.

Endocytosis, Phagocytosis, and Autophagy

• Molecular details of phagocytosis by professional and non-professional cells are introduced. The "eat me," "don't eat me" and "find me" signals in the removal of apoptotic cells are described. Clathrin-mediated and clathrin-independent mechanisms of endocytosis are discussed.

Receptors

• This lecture will present an overview of signal transduction including a discussion of the components involved, different type of signaling as well as divergence and convergence in signaling pathways. The second part of the lecture will focus on the types of receptors in cell signaling, how they function, how they are turned on and turned off and how they can be studied in the lab.

Calcium and cAMP Signaling

• This lecture focuses on the cellular structures and mechanisms responsible for the generation and modulation of Ca signals. Free cytosolic Ca is a crucial second messenger for metazoan cells. A large number of cellular events, ranging from secretion and motility to proliferation and death are modulated by the spatial and temporal characteristics of Ca signals.

G Proteins

• This lecture will cover G-protein structure, mechanism of action, and function. Examples of the role of G proteins in normal cell signaling and in disease processes will be provided with a major focus on G-protein coupled receptors (GPCRs).

Membrane Transport

• The basic physiochemical principles of solute diffusion across membranes are introduced. The major classes of transport systems (Passive or Facilitated Diffusion, Cotransporters or Secondary Active Transporters, Ion Pumps or Active transporters) are discussed, with examples of each type. Structural features of membrane transporters are also presented.

Membrane Potentials and Action Potentials

• The basics of diffusion or Nernst potentials are introduced, and then this is extended to cases where more than one ion is permeant. Hodgkin-Katz-Goldman framework for generation of membrane potentials. Ionic basis of action potentials, with an emphasis on the Hodgkin-Huxley experimental underpinnings. Basics of synaptic transmission.

Lipids Signaling

• Membrane homeostasis requires signaling mechanisms that respond to membrane stress and maintain proper levels of phospholipids and sterols. Lipids such as sphingosine-1-P play roles in intercellular signaling, while others such as ceramide and diacylglycerol have intracellular signaling roles. Selected lipid signaling pathways, from yeast to humans, and their role in disease and therapy, will be discussed.

Protein Kinases and Phosphatases

• The first part of this lecture will cover the biochemistry of phosphorylation and the structure, activation and regulation of members of the protein kinase families (Ser-Thr kinases, tyrosine kinases) and the role of protein kinases in DNA repair, cell structure and motility. The second part of this lecture will then focus on structure, function, specificity, trafficking and regulation of the major classes of protein phosphatases.

Integrins and Extracellular Matrix

• Integrins are principal receptors used by cells to bind to extracellular matrix (ECM). Integrin/ECM interactions produce mechanical attachments as well a produce intracellular signals that can influence almost any aspect of cell behavior. We will focus on the molecular, cell biological and pathological role of integrin/ECM interactions.

Apoptosis

• This lecture will cover the definitions of apoptosis and necrosis, the morphological and biochemical characteristics of these forms of death, the role of apoptosis, the fate of apoptotic cells, the caspase and Bcl-2 families of molecules, death receptor signaling and mitochondrial participation in apoptosis.

Mitosis/Meiosis/Recombination

• Chromosome pairing
• Synaptonemal complex formation and genetic recombination during meiosis
• Coordination of these processes with meiotic cell cycle progression
• Interhomolog interactions occurring during meiotic prophase and necessary for reductional chromosome segregation at the first meiotic division
• Homologous chromosome pairing
• Assembly of the synaptonemal complex
• Genetic recombination
• Formation of chiasmata

Cell Cycle

• A cell divides by utilizing a precise pathway of distinct orderly events, in which it duplicates its contents and then divides to produce two cells. This cycle of duplication and division is the essential mechanism by which all living cells divide. This lecture will discuss the complex network of regulatory proteins that control this process of cell division in eukaryotic cells.

Development and Differentiation

• This lecture will cover the basic morphogenetic events that shape the early embryo and the basic mechanisms that direct the specification and differentiation of cells in the embryo. Morphogenetic movements of embryonic cells will be correlated with disease processes in the adult.

Cellular Senescence

• Cellular aging or senescence has been identified as a tumor control mechanism that seems to be vital to preventing tumor formation. However, there are consequences to the presence of senescent cells within a tissue that are thought to contribute to age-related loss of function. These lectures will provide information regarding cellular aging, the cellular mechanisms involved and the functional changes that occur as a result. Specific examples of organ function that may be compromised as a result of the accumulation of senescent cells will be discussed.

Biology of Stem Cells

• The goal of this lecture is to cover basic aspects of stem cell biology. This lecture will discuss topics including stem cell potency, define self-renewal and differentiation and explore the role of the stem cell niche in regulation of stem cell function and maintenance. The role of stem cells in regeneration is currently being explored and is important for potential use of stem cells therapeutically. How stem cells contribute to regeneration including the presence of stem cells in tissues, dedifferentiation, and trans-differentiation as regeneration mechanisms will be considered.

Therapeutic Stem Cells

• The goal of this class is to introduce the students to the emerging fields of stem cell therapy and regenerative medicine. The lecture will present the therapeutic challenges and opportunities associated with the use of stem cells. The aim is to understand the steps leading to clinical trials with emphasis on transplantation strategies and examples derived from the nervous system.

Genomics I and II

• Analysis of complete genome sequences and use of the information for whole genome expression analysis and genetic analysis
• Analysis of recently completed genomes and genomic studies to illustrate how to sequence a genome
• Approaches to gene prediction
• Types and use of microarrays for whole genome expression analysis

Gene Inheritance and Mapping

• Genetic maps allow a connection to be made between structure and function: gene-> protein -> function
• Genetic maps, comparing and contrasting different kinds of maps, mapping methods
• Analysis of patterns of inheritance
• Application of genetic mapping to understanding genetic defects associated with disease

Transgenic Applications I and II

• Model transgenic organisms in research
• Generation, use and analysis of transgenic plants (Agrobacterium), worms (C. elegans), and insects (Drosophila)
• Transgenic mice
• Gene targeting strategies to construct 'knockout' and 'knockin' organisms

Proteomics

• Sample preparation involving sub-cellular fractionation, affinity isolation of post-translationally modified peptides and protein complexes for analysis by mass spectrometry
• Peptide chromatography coupled to mass spectrometry
• Proteomic data acquisition and peptide sequencing/interpretation with automated search algorithms and manual inspection
• Quantitative proteomics with differential isotopic labeling

Bioinformatics I, II, III

• Understanding the central dogma from a bioinformatics perspective
• Review of available databases and their applications in life sciences
• Concepts of homology and phylogenetic relationships
• Basics of sequence alignment and BLAST tools
• Protein structure and modeling
• Understanding mutations in the context of structure and function
• Hands on training on using bioinformatics tools, on BLAST tools and analysis, and on secondary and tertiary structure prediction

Integrated Systems

• Interactive, interdisciplinary small group exercises in the general areas of neuroscience, immunology and cancer biology

 
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