Introduction to Pathopharmacology and Genetics

Introduction to Pathopharmacology

Overview of Course Structure

The course is divided into two parts:

• Part One: Pathology

• Part Two: Pharmacology
  The structure will alternate between studying pathology and pharmacology throughout the course.

Focus of Today's Lecture

Main topics:

1. Human Cell

2. Cellular Injury

3. Adaptation

4. Death
   Discussion will include:

• Cellular communication

• Pathways leading to cellular adaptation and injury

• Gangrene

Instructor Information

Professor: Chajokio Keke

Course Objectives

The objectives of this course are to:

1. Review the basic human cell structure focusing on aspects relevant to pathology.

2. Understand key organelles:

   • Nucleus

   • Mitochondria

   • Plasma Membrane

3. Discuss the DNA replication cycle and the role of enzymes, particularly p53, in cellular function and cancer risk.

4. Explore cellular communication and its importance in cellular function and adaptation.

5. Examine types of cellular adaptations and the progression to cellular injury and death.

6. Define gangrene and its types.

Key Components of the Human Cell

Plasma Membrane

• Composition: A barrier that surrounds the cell.

• Functions:

  • Facilitates communication

  • Nutrient transport

  • Maintains cellular integrity

Cytoplasm

• Description: Gel-like substance within the plasma membrane.

• Function: Contains organelles where metabolic processes occur.

Nucleus

• Function: Control center of the cell containing DNA.

• Controls the transcription of DNA into RNA.

Mitochondria

• Description: The powerhouse of the cell.

• Function: Production of ATP (energy) through cellular respiration.

Human Cell Functions

Cells work in coordination as multicellular organisms. Key functions include:

• Movement: E.g., muscle contractions

• Sensory perception: E.g., environmental response

• Communication: E.g., neuronal signals

• Absorption: E.g., oxygen intake

• Secretions: E.g., hormones, enzymes

• Excretion: E.g., removal of toxins

• Respiration: E.g., utilization of oxygen and glucose

• Reproduction: Cell replication (except for highly specialized cells like neurons)

Key Cellular Processes

DNA Replication Cycle

Stages of the cell cycle:

1. G0 Phase: Non-dividing state.

2. G1 Phase: Cell growth and preparation for DNA synthesis.

3. S Phase: DNA synthesis and replication.

4. G2 Phase: Preparation for mitosis (M Phase).

5. M Phase: Mitosis and cytokinesis, resulting in two daughter cells.

Transcription Process

• RNA Synthesis: The process of copying specific segments of DNA into messenger RNA (mRNA).

• mRNA guides protein synthesis at ribosomes.

Protein Synthesis

• mRNA moves to ribosomes, where transfer RNA (tRNA) facilitates the assembly of amino acids into proteins.

Errors in Cellular Processes

• Mutations can occur during DNA replication, leading to diseases such as cancer.

• Specific examples include:

  • Cancer: Uncontrolled cell proliferation due to genetic mutations.

  • Hemophilia B: Genetic condition resulting from mutations.

• Importance of p53 Protein: Acts as a tumor suppressor, regulating the cell cycle and DNA repair.

• Mitochondria also have their own DNA which can mutate, leading to mitochondrial diseases.

Cellular Metabolism

• Catabolism: Breakdown of substances to generate energy (e.g., from glycogen to glucose for ATP production).

• Anabolism: Building and synthesizing substances (e.g., synthesizing glycogen from glucose).

• Enzymes: Proteins catalyzing biochemical reactions; proper function requires accurate DNA sequences.

• Substrate Hydrolysis: Digestion of carbohydrates, proteins, and fats into simpler molecules for metabolism.

Plasma Membrane Structure

• Phospholipid Bilayer: Contains hydrophilic (water-attracting) heads and hydrophobic (water-repelling) tails.

• Characteristics:

  • Fluid mosaic model: Membrane is not rigid, allowing flexibility and movement.

  • Embedded proteins facilitate transport and communication (e.g., channels for glucose transport).

Transport Mechanisms

1. Active Transport: Requires energy (ATP) to move molecules against their concentration gradient (e.g., sodium-potassium pump).

2. Passive Transport: Does not require energy; substances move freely across the membrane (e.g., osmosis for water).

Cell Communication

Importance of Communication Between Cells

• Essential for maintaining homeostasis and coordinated activity.

Types of Signaling

1. Autocrine: Cell signals itself.

2. Paracrine: Cell signals nearby cells.

3. Endocrine: Hormonal signals across long distances instigated by glands.

Cellular Injury

Causes of Cellular Injury

1. Physical Agents: Mechanical forces (e.g., trauma), extreme temperatures (hypothermia/hyperthermia).

2. Radiation: Harmful ionizing radiation affecting cellular structures (e.g., DNA damage).

3. Chemical Agents: Toxic substances (e.g., heavy metals like lead, carbon tetrachloride).

4. Biological Agents: Viruses, bacteria, and parasites causing infection and inflammation.

5. Nutritional Imbalances: Excess or deficiencies affecting metabolic processes (e.g., too much cholesterol).

6. Free Radicals: Highly reactive molecules causing oxidative stress that damages cells.

Types of Cellular Injury Responses

• Reversible Injury: Cells can recover from mild stress or damage (e.g., temporary hypoxia).

• Irreversible Injury: Severe damage leading to cell death (e.g., necrosis or apoptosis).

Calcification Related to Cellular Injury

• Calcification: Pathological deposition of calcium salts in tissues.

  • Dystrophic Calcification: Occurs in damaged, degenerating, or necrotic tissues despite normal blood calcium levels.

  • Metastatic Calcification: Occurs in normal tissues due to abnormally high levels of calcium in the blood (hypercalcemia).

Cell Adaptation Mechanisms

1. Atrophy: Decrease in cell size due to decreased workload or stimulation.

2. Hypertrophy: Increase in cell size indicating greater workload (e.g., muscle growth).

3. Hyperplasia: Increase in cell number (e.g., skin cells due to chronic irritation).

4. Metaplasia: Change of one cell type to another (replacing dysfunctional cells).

5. Dysplasia: Abnormal growth of cells with loss of cellular orientation and structure.

Types of Cell Death

• Apoptosis: Programmed cell death, a controlled process not damaging surrounding tissues.

  • Examples include the removal of webbing during development or T-cell mediated destruction of infected cells.

• Necrosis: Uncontrolled cell death due to injury, leading to inflammation and tissue damage.

Gangrene

Expansion of necrosis typically involving large areas of tissue.

Types of Gangrene:

1. Dry Gangrene: Associated with ischemia, leading to shriveled skin and brownish appearance.

2. Wet Gangrene: Due to bacterial infection, characterized by swelling, blackened tissue, and foul odor showing rapid spread.

Key Takeaways

• Pathology is essential for understanding how cellular functions malfunction, leading to disease.

• Communication between cells is crucial for maintaining homeostasis.

Genetics and Genetic Disorders in Pathophysiology

Introduction to Genetics

The lecture focuses on:

1. Genetics and genetic disorders (congenital disorders).

   • Exploring how genetic variations and changes lead to diseases manifesting at or before birth, or later in life.

2. Understanding the relationship between chromosomes, genes, and DNA.

   • Delving into the hierarchical organization of genetic material from the smallest units to its packaging into chromosomes.

3. The role of genetic mutations in disease and inheritance.

   • Investigating how permanent changes in DNA affect gene function and how these alterations are inherited.

4. Factors affecting genetic makeup.

   • Examining both intrinsic (e.g., parental genetics) and extrinsic (e.g., environmental exposures) elements influencing genetic profiles.

5. Gene assessments in healthcare.

   • Discussing methodologies for analyzing genetic material and applications in diagnosis and personalized strategies.

Objectives of the Lecture

Reaffirm understanding of:

• Chromosomes, genes, and their relationship with DNA.

• Gene expression and phenotype: Explaining the flow of genetic information from DNA to RNA to proteins depicting observable traits.

• Modes of inheritance: Detailing patterns of gene transmission from parents to offspring (e.g., autosomal dominant, autosomal recessive, X-linked, mitochondrial).

• Impact of genetic mutations on inheritance: Analyzing how DNA alterations affect inherited traits or disease susceptibility.

• Genetics and pathology relationship.

• Factors influencing genetic mutations: Environmental and genetic agents leading to mutations.

Key Genetic Concepts

Chromosomes and DNA

• Humans have 23 pairs of chromosomes (46 total):

  • Autosomal chromosomes (pairs 1-22): Non-sex chromosomes present in both genders with genes for most traits.

  • Sex chromosomes (23rd pair): Determine biological sex (XX for females and XY for males).

Importance of Cell Types

• Somatic cells: Non-reproductive, containing a diploid set of chromosomes; reproduce via mitosis.

• Gametes: Haploid cells (sperm and eggs) produced through meiosis, introducing genetic variation.

DNA Structure

• DNA (Deoxyribonucleic Acid): Double-helix polymer of nucleotides (deoxyribose, phosphate, nitrogenous bases: A, T, C, G).

• Base pairing: A-T and C-G are fundamental for replication and genetic coding.

Genes and Alleles

• Genes: Units of heredity that encode proteins/functional RNA, determining various cellular functions.

• Alleles: Variants of a gene at the same locus on homologous chromosomes; combinations influence genotype and phenotype.

  • Example: Blood type gene with alleles IA, IB, and i.

Important Terminology

Genetic Mutations

• Gene mutation: Permanent alterations in DNA sequences, that range from single base pair changes (point mutations) to large insertions or deletions.

• Mutations lead to polymorphisms if they occur in more than 1% of the population.

Types of Gene Mutations

1. Point mutations: Silent, missense, nonsense.

2. Frameshift mutations: Insertions or deletions that alter sequences.

3. Chromosomal mutations: Changes in structure or number of chromosomes (aneuploidy, translocations).

Types of Chromosomal Disorders

1. Aneuploidy: Abnormal number of chromosomes.

   • Monosomy: Absence of one chromosome from a pair (e.g., Turner syndrome).

   • Trisomy: Presence of an extra chromosome (e.g., Down syndrome).

2. Chromosomal Rearrangements:

   • Deletions: Missing portions.

   • Duplications: Extra genetic material.

   • Translocations: Segments moving between chromosomes.

   • Inversions: Reversal of chromosome segments.

   • Ring chromosomes: Circular structures formed by breaks in the chromosome.

Genetic Penetrance

• Definition: The proportion of individuals with a genotype that expresses the associated phenotype.

• Example: 80% penetrance indicates that 80% of those with the mutant gene show symptoms.

Gene Expression

• The flow from DNA to functional products (proteins/non-coding RNA) through transcription and translation. Regulatory mechanisms allow adaptation and specialized functions.

Autosomal vs. X-linked Inheritance

Autosomal Inheritance

• Refers to traits located on one of the 22 autosomal chromosomes.

• Affecting both genders equally and expression independent of gender.

X-linked Inheritance

• Traits located on the X chromosome.

• Males are more frequently affected by X-linked recessive disorders because they lack a second X chromosome.

Modes of Inheritance

Genotype vs. Phenotype

• Genotype: Complete set of genes represented by combinations of alleles.

• Phenotype: Observable characteristics influenced by the genotype, environmental factors, and interactions among multiple genes.

Examples of Punnett Squares

• Visual tools for predicting genotype/phenotype probabilities in offspring.

• Autosomal dominant inheritance: Manifesting with one mutated allele.

• Autosomal recessive inheritance: Manifesting with two copies of the mutated allele (carriers typically asymptomatic).

Genetic Disorders

Congenital Disorders

• Conditions present at birth from genetic mutations, chromosomal abnormalities, or environmental factors.

Examples

1. BRCA1 and BRCA2 Mutations and Cancer:

   • Function: Produce tumor suppressor proteins that repair DNA.

   • Effect: Mutations lead to significantly increased cancer risk (breast, ovarian, prostate).

   • Management: Intensive screening, prophylactic surgeries.

2. Sickle Cell Anemia:

   • Description: Autosomal recessive disorder due to mutation in the HBB gene, causing distortion of red blood cells.

   • Effect: Leads to anemia, pain crises, and organ damage.

   • Management: Hydroxyurea and pain management.

3. Hemophilia A:

   • Description: X-linked recessive disorder due to mutations in the F8 gene affecting blood clotting.

   • Effect: Impairs blood clotting; males are primarily affected.

   • Management: Intravenous replacement therapy, newer non-factor therapies.

4. Von Willebrand Disease (VWD):

   • Description: Impairs platelet function; usually autosomal dominant.

   • Effect: Variability in bleeding severity.

   • Management: Desmopressin and concentrates.

Environmental and Multifactorial Influences

Teratogens

• Agents causing physical anomalies in embryos/fetuses due to prenatal exposure.

• Notable teratogens include alcohol (causing Fetal Alcohol Syndrome), radiation, and infectious agents (e.g., Zika virus).

Key Teratogen Examples

1. Zika Virus:

   • Effect: Microcephaly and other congenital defects.

   • Management: Mosquito control, supportive care.

2. Rubella:

   • Effect: Congenital Rubella Syndrome with several serious outcomes.

   • Prevention: Vaccination.

Genetic Testing

Purpose

• Analyzes DNA, RNA, or proteins to detect genetic variations.

• Includes:

  • Diagnostic testing: Identifying genetic causes of symptoms.

  • Predictive testing: Assessing risk without current symptoms.

  • Carrier screening: Finding individuals who carry genes for recessive disorders.

  • Prenatal testing: Detecting conditions in fetuses.

Concerns

• Ethical, Legal, and Social Implications (ELSI):

  • Privacy, discrimination, psychological impact, informed consent, and accuracy.

  • Access and justice regarding testing and costs.