Core Concepts

Introduction to the course including tree of life, evolution, important molecules for life, and fundamental concepts of cell structure and function.

DNA and Chromosomes: DNA and RNA Structure

DNA and RNA structures and their relevance to cellular function and to widely used molecular biology methods.

DNA and Chromosomes: DNA Replication

Basics of DNA replication, semiconservative replication, replication forks, origin of replication, semi-discontinuous synthesis, primers, proof-reading, proteins of DNA replication, the replication of a bacterial chromosome; detailed look at elongation and initiation of DNA replication, and replication of eukaryotic chromosomes including the replication of the ends of linear chromosomes.

DNA and Chromosomes: DNA Mutation, Repair and Recombination

An overview of types of DNA damage. DNA damage results from both internal and external assaults on the cell. Examples of internal DNA damage: errors of DNA polymerase during the normal process of DNA replication; DNA damage caused by reactive products of cellular metabolism. Examples of external DNA damage: various environmental factors such as alkylating agents, toxic hydrocarbons and pesticides, UV light and ionizing radiation that target and modify our DNA in harmful ways. Definition of DNA damage and mutations. DNA damage may lead to cell death or mutations that may cause different deceases including cancer. There are several cellular pathways responsible for neutralizing DNA damage and repair of damaged DNA. We will learn the major mechanisms how these pathways operate.

Introduction to Proteins

Amino acid structure, classifications, abbreviations; acid-base properties of amino acids. Structure (with forces that stabilize) and function of proteins: primary, secondary, tertiary, and quaternary structure (with emphasis on peptide bond formation and on protein folding). Enzymes are a special class of proteins. Protein interactions and interaction networks on and in cells; fundamentals of conformational scaffolds, complementary binding surfaces and structural adaptability in protein recognition and assembly; interaction and conformational cascades in protein machines; cooperative mechanisms of interaction; protein interactions and function in antibodies and cell receptors; methods for measuring and characterizing protein interactions.

From DNA to RNA: Transcription

(I) Transcriptional overview, (II) Transcription in prokaryotic cells, (III) Eukaryotic transcription, (IV) Transcriptional control, (V) Gene expression. (V) Gene expression (continued) and (VI) Regulation of Eukaryotic gene transcription.

Types and structure of RNA; mRNA processing in eukaryotic cells, including capping, splicing, polyadenylation, transport, and degradation; processing of rRNA and tRNA.

From DNA to RNA: Epigenetics

This lecture will focus on how changes in DNA methylation, the modifications of histones (methylation, acetylation) and the structure of chromatin contribute to the regulation of gene expression. These can be heritable changes in gene activity that are independent of changes in DNA sequence. Epigenetic modifications in disease states as well as therapeutic applications will be discussed.

From mRNA to Proteins and Beyond: Translation

• Protein synthesis, the genetic code, the mechanism of protein synthesis, a comparison of the key features of prokaryotic and eukaryotic translation machinery, and regulation and inhibition of protein synthesis
• Regulatory aspects of translation, translational block of maternal mRNA, subcellular localization of mRNAs destined for different parts of the cell, (using examples in the yeast and neurons)
• Regulation of gene expression in eukaryotes by small RNAs, with emphasis on the role of small interfering RNAs in transcriptional and post-transcriptional gene regulation; introduction to prokaryotic CRISPR-Cas systems
• Protein processing: protein folding, cleavage, and covalent modification. Protein trafficking to the nucleus, mitochondria and peroxisome

From mRNA to Proteins and Beyond: Degradation

The lecture will focus on how proteins are targeted for degradation by ubiquitin-mediated proteolysis. The role of protein ubiquitin and ubiquitin-like modifications in the cellular processes will be discussed.

From ER to Golgi and Beyond

The specific mechanisms and players involved in transport of proteins for secretion or localization to the plasma membrane, lysosomes, and the endoplasmic reticulum will be described, including experimental approaches used to uncover the transport processes.

Protein trafficking from the ER through the Golgi Complex via the secretory pathway will be described. In particular, the dynamic nature of the Golgi will be discussed, including vesicle formation, vesicle targeting, vesicle fusion, vesicle vs. cisternal maturation and sorting at the Trans-Golgi Network.

Intracellular Vesicular Trafficking: Endocytic Trafficking

This lecture will provide an overview on the intracellular vesicle movement that involves vesicular endosome formation, processing and recycling. Various major pathways and essential players will be discussed. Examples of diseases that are associated with defective intracellular vesicular movement will be introduced.

How to Work with DNA: Cloning

Short introduction into manipulation of DNA, construction of a plasmid, cloning techniques.

How to Work with DNA: Transgenics

This lecture discusses genetic approaches through the use of transgenic cells and organisms. It covers the methods for inserting and deleting genes and the use of transgenic models. A mouse will be used as an example of a model transgenic organism.

Cytoskeleton: Microtubule Dynamics

This lecture will introduce microtubule biology and focus on mechanisms that regulate microtubule dynamics in cells.

Cytoskeleton: Microtubule Basis of Intracellular Transport

This lecture will focus on molecular motor proteins that convey cargo along microtubules and actin filaments, together with a discussion on how microtubule arrays become organized so that transport of cargoes is polarized within cells.

Cytoskeleton: Actin Filaments

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.

Mechanisms of Cell Communication and Signaling

This lecture will present an overview of signal transduction including a discussion of the components involved, different types 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.

G-proteins and Second Messenger Systems

This lecture will discuss some of the central signaling processes involved in cellular action, focusing specifically on G-protein coupled receptor (GPCR) mediated signaling and the generation and activity of second messengers. The first hour will discuss G-protein structure, mechanism of action and the role of G proteins in normal cell signaling and disease. The second hour will focus on the role of the critical second messengers Ca2+ and cAMP in various signaling processes.

Proteins Kinases, Phosphatases and Lipid Signaling

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.

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.

Ion Channels: Ionic Basis of Membrane Potentials and Action Potentials

Principles of diffusion and transport of solutes across membranes will be discussed in general. The focus will be on passive and active membrane properties. This will include Nernst potentials, the Hodgkin-Katz-Goldman framework for the establishment of resting membrane potential, and generation of action potentials based on Hodgkin-Huxley experimental underpinnings of voltage-gated ion channel properties and related ion movement. Experimental manipulations described will be placed into physiological context.

Juxtacellular Signaling: Integrins, Extracellular Matrix and Gap Junctions

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.

Integrins are principal receptors used by cells to bind to extracellular matrix (ECM). Integrin/ECM interactions produce mechanical attachments as well as 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.

Metabolism: Glucose Metabolism

Structure and function of glycogen, storage sites, pathways of synthesis and degradation, regulation of the pathways by covalent modification and allosteric effectors. Cellular uptake and utilization of glucose, regulation of glycolysis (with an emphasis on gluco/hexokinase, phosphofructokinase, pyruvate kinase); metabolism of fructose and galactose; pentose phosphate pathway; gluconeogenesis reactions, regulation, compartmentalization.

Metabolism: ATP Synthesis

Overview of catabolic pathways and central role of acetyl CoA in cellular formation of ATP as an energy source in cells; molecular organization, cellular localization, and regulation of enzyme systems that convert pyruvate to ATP; enzyme components, structural organization and regulation of the pyruvate dehydrogenase multienzyme complex that forms acetyl CoA from pyruvate; tricarboxylic acid cycle, its multienzyme molecular organization and reactions leading from acetyl CoA to respiration and phosphorylation; biological oxidation and reduction; mitochondrial electron transport (respiratory chain), its organization in membranes and the function of ETC protein complexes to reduce oxygen and drive the formation of proton gradients in mitochondria ; the ATP synthase protein machine and its mechanism of function and regulation in the oxidative phosphorylation that leads to ATP.

Metabolism: Lipid Metabolism

Lectures will include biosynthesis, trafficking and catabolism of lipids. Topics covered include fatty acid biosynthesis via the fatty acid synthase, beta-oxidation/fatty acid degradation, ketogenesis, peroxisomal degradation, cholesterol biosynthesis and the generation of steroid hormones, different lipid classes including triacylglycerides, phospholipids, sphingoglycolipids, eicosanoids, and trafficking of lipids through the body.

Metabolism: Amino Acid Metabolism

An overview of amino acid metabolism with an emphasis on the amino acid pool, nitrogen catabolism, urea cycle, the use of alpha-keto acid skeletons in energy metabolism (gluco- and ketogenic amino acids), metabolism of branched-chain amino acids highlighting the production and roles of glutamine and alanine, and metabolism of aromatic and sulfur-containing amino acids.

Metabolism: Review and Integration of Intermediary Metabolism

A refocus on the “big picture”; role of liver, muscle, adipose and brain in the fed and short-term fasted states; review (overview) of the key pathways of the fed and fasted states with emphasis on regulation, key sites and molecules, and adaptation to long-term fasting with a focus on tissue interrelationships.

Replication of the Cell

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.

Replication of the Cell

Mitotic and meiotic cell division, their differences and similarities. Pairing of homologous chromosomes, formation of synaptonemal complex and chiasmata during meiosis prophase I, coordination of these processes with meiotic cell cycle progression. The role of homologous recombination in reductional chromosome segregation during the first meiotic division. Cellular mechanisms that enhance the accuracy of chromosome segregation in meiosis and the risk of meiotic abnormalities.

Life and Death of the Cell

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.

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.

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 energy generation, the importance of mitochondria in regulating calcium levels in the cell as well as the triggering of the apoptotic pathway is described.

Life, Death and Aging of the Cell

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.

Stem Cells: From Basic Science to Therapeutics

The goal of this lecture is to cover basic and translational aspects of stem cell biology. We will discuss the properties of stem cell with respect to potency, self-renewal and differentiation, and emphasize the diversity of stem cells depending on tissue of origin and the protocols used to prepare and manipulate them. The application of stem cells will be presented in the context of mechanistic studies and therapeutics including formation of organoids, transplantation and design of clinical trials.

The goal of this class is to introduce the students to the emerging fields of regenerative medicine in the context of stem cell biology and therapy and become familiar with terms associated with stem cells and clinical trials. The lecture will present the therapeutic challenges and opportunities facing the application of stem cells from the research laboratory to the clinic. The aim is to understand the steps leading to clinical trials with FDA approved examples.

Immunology 101

Immune Cell Biology: Basic
The major role of our immune system is to provide us with a defense mechanism to prevent infection with pathogenic microbes and to clear established infections. An effective response to an invading pathogen involves a complex, coordinated set of interactions of various molecules, cells and tissues. We will discuss the early, first line of innate defenses to infection and how this response develops over time into a customized, pathogen-specific adaptive immune response. We will describe the primary cells and tissues of the body that comprise the immune system. We will discuss the basic functions of these cells of the immune system, their distribution throughout the body and how these cells interact and communicate with one another to clear infectious agents.

Immune Cell Biology: Applied
Cells and molecules of the immune system can be used to advance basic science research across many disciplines and to improve patient outcomes in the context of infectious disease as well as non-infectious diseases. We will discuss general approaches to prevent infectious disease by manipulation of the immune systems through vaccination. We will discuss state-of-the-art approaches to produce monoclonal antibodies of defined specificity for use in the research lab, in the diagnostic lab and in the clinic. Finally, we will discuss recent innovations in applied immunology for the treatment and cure of various cancers.

 
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