This course will
cover multidisciplinary approaches to address essential questions concerning cellular
and molecular mechanisms of disease. There is a focus on important cellular
processes including ER stress, mitochondrial dysfunction, protein synthesis and
turnover, and DNA damage responses. Malfunctions within the pathways regulating
these processes, often resulting from mutations in key proteins, cause a range
of human diseases including cancer. To understand the structures, mechanism and
regulations of the key complexes involved, we will cover a variety of methodologies from various disciplines, including biochemistry, cell and molecular biology, genetics, development, medicine and environmental
science. As earlier lectures provide the foundation for the understanding of
later lectures, continuous presence and active participation will be essential.
The course focuses on how experimental data are obtained and interpreted, which
should make the module especially valuable to students who are interested in
experimental science.
Intended learning outcomes
ù
To develop an understanding of the causes and mechanisms of disease and
the associated alterations of structure and function.
ù
To develop skills of observation, interpretation, and integration needed
to analyze human disease. When provided with the clinical history, the
anatomical lesions, and the laboratory data of a patient, to determine the most
likely diagnosis and explain the pathogenesis of the disease
Teaching and learning methods
ù This is not a lecture course. It is impossible to cover
all of the textbook material in a classroom setting. Students must read and
learn from the book. It is recommended
that you read the “Recommended” textbooks.
ù Instruction is provided in many formats: small
groups (tutorials), with computer modules, case studies, all of which are
designed to help you learn to utilize information acquired from reading.
ù An outline of the course and objectives for each
lecture and section follows this introduction.
Journal Article Analysis
Each student will
be assigned a published peer reviewed disease journal article to analyze. The
analysis will be due two weeks after the date the article was received. The
analysis must be typed. The analysis should be 2-4 pages in length. The
analysis must include the following:
ù Title page
- Include name, date, course title and number, instructor, title of article,
authors Introduction - Summary of what the article is about; How is the work
novel? What questions are the authors trying to answer?
ù Methods
- Describe the experimental design of the study and any model systems used
ù Results
- Present the experimental findings of the authors
ù Discussion
- Discuss the results presented by the authors and state whether the results
were expected or unexpected
ù Conclusion
- What have you learned from the article? Do you feel the article was well
written? How should the article be modified?
Group' Presentation
Each student will
be assigned a published peer reviewed disease journal article to analyze. The
analysis will be presented orally during class. Articles will be assigned at
least two weeks prior to the date of presentation. Presentations should be
prepared in PowerPoint. Each presentation will be approximately 15 minutes
long. There will be a 5 minute Question and Answer period following the
conclusion of each presentation. The presentations must include the following:
ù Title slide - Include names of group members, date, title of article,
author's names, and journal title
ù Background
- Include pertinent background information so the audience will be able to
follow the presentation easily. Example: If your article discusses lung cancer,
I would expect you to include some general statistics on this type of cancer
and current treatments used.
ù Methods
- Explain what methods were used in the article
ù Results
- Present each figure separately. Explain what experimental question the
authors are trying to address
ù Conclusion
- What conclusions did the authors make?
Methods of assessments
There
will be three exams during the course. The exams will each cover one-third of
the material, including basic concepts learned from discussion of the primary
literature. Graduate students enrolled in the course will be required to
contribute to in class explanation of advanced techniques related to the
research articles. The final cumulative grade will be based on:
ù Quizzes 5%
ù Papers and class
participation: 20%
ù Midterm exam 1: 25%
ù Midterm exam 2: 25%
ù Final exam
(non-cumulative): 25%
Your
lowest quiz score will be dropped. Final grades will likely be assigned
according to a straight percentage distribution: A = 90-100%; B = 80-89.9%; C =
70-79.9%; D = 60-69.9%; F =
Attendance
Students
are expected to attend all classes. This is an interactive course that is
research oriented and is heavily based on discussions. If you do not attend,
you will not be able to participate. The tolerated limit of necessary absences
is three class meetings.
Part- I: Lectures Outlines
1. The Nature and Investigation of Diseases
2. Pathogens and Virulence
3. Infectious Diseases and Treatments
4. Disorders of the Immune System
5. Diet and Disease
6. Disorders of the Gastrointestinal Tract, Pancreas,
Liver and Gall Bladder
7. Disorders of the Blood
8. Disorders of the Cardiovascular System
9. Genetic Diseases
10. Membrane, Organelle and Cytoskeletal Disorders
11. Aging and Disease
12. Neurodegenerative Disorders
a.
Introduction,
Overview, Historical Perspective
Reading for
class discussion:
ù
Bossy-Wetzel, Schwarzenbacher, Lipton (2004) Molecular pathways to
neurodegeneration. Nature Medicine S2-S9.
b.
β-amyloid
Hypothesis and Tauopathies
Reading for
class discussion:
ù
Wirths, Multhaup, Bayer (2004) A modified beta-amyloid hypothesis:
intraneuronal accumulation of the beta anyloid peptide--the first step of a
fatal cascade, Journal of Neurochemisty 91(3):513-520.
c.
α-Synucleinopathies
and Polyglutamine Repeat Diseases
Reading for
discussion:
ù
Gunawardena and Goldstein (2005) Polyglutamine diseases and transport
problems: deadly traffic jams on neuronal highways. Archives of Neurology
62(1):46-51.
ù
Everett and Wood (2004) Trinucleotide repeats and neurodegenerative disease.
Brain 127(Pt 11):2385-2405.
ù
Morfine, Pigino, and Bradley (2005) Polyglutamine expansion diseases: failing
to deliver. Trends in Molecular Medicine 11(2):64-70.
d.
Amyotrophic
Lateral Sclerosis and Superoxide Dismutase; Creutzfeldt-Jakob and Prion Protein
Diseases.
Reading for
class discussion:
ù
Lindgerg, Bystrom, Boknas, Anderson and Oliveberg (2005) Systematically
perturbed folding patterns of amyotropic lateral sclerosis (ALS)-associated SOD-1
mutants. PNAS 102(28):9745-9750.
e.
Genetic
Contributions to Neurodegenerative Disease
Reading for
class discussion:
ù
Spire and Hannon (2005) Nature, nurture, and neurology: gene-environment
interactions in neurodegenerative disease. FEBS J 272(10):2347-2361.
ù
Class Activity: Cell Death Pathways
f.
Axonal
Transport Defects. Misfolding and Aggregation of Disease Proteins
Reading for
class discussion:
ù
Roy, Zhang, M.-Y Lee, Trojanowski (2005) Axonal transport defects: a
common theme in neurodegenerative diseases. Acta Neuropathol 109-5-13.
g.
Oxdative
Alterations. Mitochondrial Dysfunction
Reading for
class discussion:
ù
Facheris, Beretta, and Ferrarese (2004) Peripheral markers of oxidative
stress and excitotocicity in neurodegenerative disorders: tools for diagnosis
and therapy? J Alzheimers Dis 6(2):177-184.
h.
Future
Strategies – Stem Cells and Gene Therapy
Reading for
class discussion:
ù
Ruszynsk, Thai, Pay, Salmon, Sang, Bakay, et al (2005) A Phase I clinical
trial of nerve growth factor gene therapy for Alzheimer’s disease. Nature Medicine
11(5): 551-556.
ù
Lindvall, Kokaia, Martinez-Serrano (2004) Stem cell therapy for human neurodegenerative
disorders-how to make it work. Nature Medicine Suppl:S42-50.
ù
Mohapel and Brudin (2004) Harnessing endogenous stem cells to treat neurodegenerative
disorders of the basal ganglia. Parkinsonism Related Disorders 10(5):259-264.
ù
Mendez, Sanchez-Pernaute, Cooper, Vinuela, Ferrari, Bjorklund, Dagher,
Isacson (2005) Cell type analysis of functional fetal dopamine cell suspension
transplants in the striatum and substantia nigra of patients with Parkinson’s
Disease. Brain 128:1498-1510.
13.
Remaining weeks: Oral presentations and paper discussion
Part-II: Laboratory Outline
Experimental strategies and molecular
biology techniques: Western blotting, Immunocytochemistry, RFLP, Q-RT-PCR, DNA-PCR
and direct DNA sequencing. Model systems used to study diseases: in vitro,
ex vivo, and in vivo model.
Textbook:
ù Ahmed et al. (2007).
Biology of Disease. 1st edition. Taylor & Francis Group,
New York.
Recommended Textbooks:
ù Robbins and
Cotran Pathologic Basis of Disease –Kumar, Abbas, Fausto W.B. Saunders, 8th
ed., 2010.
ù Harrison’s
Principles of Internal Medicine, McGraw-Hill, 17th Edition. This edition is in
electronic form is also available in the library on MD consult
