Final Flashcards
1
Q
what are 2 ways that cortisol can act on the pit. and hypothalamus
A
- Fast - change of cortisol levels nonnuclear
2. Slow - change of cortisol levels nuclear
2
Q
3 ways cortisol can be regulated
A
- stress
- circadian rhythm
- feedback (ACTH + cortisol)
3
Q
how is cortisol released
A
pulsatile (combination of negative and positive control on CRH)
4
Q
when are peak levels of CRH and ACTH
A
before awakening
- decline during the day
5
Q
how does ACTH work
A
acts on the adrenal cortex rendering release of glucocorticoids, mineralcorticoids etc; there is a greater ACTH and glucocorticoid (cortisol rise in morning)
6
Q
where does circadian rhythm happen
A
hypothalamus
7
Q
what hormones (and other markers) follow a circadian rhythm
A
ACTH, cortisol, body temp, HR, work level
8
Q
why is body temp used as a marker for circadian rhythm
A
- studying hypothalamus = invasive
- body temp is easy to measure, not invasive
- HR and work level are easy to measure BUT are influenced by external influences
9
Q
what cues circadian rhythm
A
- light/dark
- stress
- sleep pattern
- feeding times
- physical work
10
Q
what dysregulates circadian rhythm
A
- Cushing’s syndrome (high cortisol levels: stress)
- liver disease
- renal failure
- drug addiction
11
Q
where does CRH (cortisol regulating hormone) come from
A
hypothalamic paraventricular nucleus (from parvocellular cells)
12
Q
where does the circadian rhythm control of cortisol secretion derive from the connections between?
A
between the hypothalamic paraventricular nucleus and the suprachiasmatic nucleus
13
Q
what do lesions in the suprachiasmatic nucleaus tissue cause
A
locomotor activity rhythm, damaged circadian rhythmicity
14
Q
what is the master clock of an organism
A
suprachiasmatic nucleus
15
Q
where does the core of the SCN receive photo input from
A
retino-hypothalamic tract
- the cells involved in SCN entrainment are different than the ones involved in vision
16
Q
where does the SCN receive non-photo input
A
- neuropeptide Y
- intergeniculate leaflet
- serotonergic projections from the median raphe nucleus
17
Q
what part of brain are sleep schedules regulated from
A
projections from the SCN to dorsomedial hypothalamus and posterior hypothalamic area
18
Q
how can the central clock of the SCN be reset
A
LIGHT OR DARK CYCLES
- feeding rhythms which depend on sleep/wake activity rhythms
- through the retino-hypothalamic tract
19
Q
what is secreted from pineal gland
A
serotonin
- gets converted to melatonin at night
20
Q
central output from SCN
A
- sleep/wake cycles
- cognitive performace
21
Q
peripheral outputs from SCN
A
- heart
- kidney
- liver
- muscle
- body temp
22
Q
pathway of SCN: from input to output… name tracts and structures
A
input (light) –> retino-hypothalamic tract –> SCN –> hypothalamic paraventricular nucleus –> output (thermoregulation, sleep/wake etc)
23
Q
what causes ACTH release
A
stress (infection, depression, trauma, pain)
24
Q
what is Cushing syndrome
A
excess cortisol - remember CRH released from hypothalamus, acts on ant. pit which releases ACTH, ACTH acts on adrenal glands producing CORTISOL
25
4 symptoms of Cushing's syndrome
1. Protein depletion (muscle wasting)
2. Fat redistribution (increased abdominal weight)
3. Mental problems (depression/mania)
4. Inhibition of bone formation (impair vit. D and metabolism)
26
causes of Cushing syndrome
| 2 causes
1. excessive endogenous production of cortisol
- ACTH dependent
- ACTH independent
2. administration of glucocorticoids for therapeutic purposes
27
different kinds of excessive endogenous production of cortisol
1. pituitary ACTH dependent (excessive secretion of ACTH in ant pit from tumour)
2. ACTH-independent (tumour in adrenal cortex)
3. ectopic ACTH (tumour)
4. ectopic CRH(tumour)
28
note about question on final ACTH what tissue????
| - don't get it but prob memorize
- muscle
- lymphoid
- connective
29
Addison's disease
hyposecretion of glucocorticoids/mineralcorticoids from adrenal cortex
-hypoadrenocorticism (too little cortisol and aldosterone)
30
what is Addison's cause and what does this lead to**
| 3
underproduction of cortisol from the adrenal cortex, leads to lack of NEGATIVE feedback on the pituitary... leads to an increase in ACTH secretion*
- stimulates melanin synthesis and bronzing of skin
- hypoglycemia
- Na+ and K+ imbalances due to aldosterone deficiency*
31
what does cortisol do
control blood sugar levels, regulate metabolism, reduce inflammation
32
where in aldosterone produced
| - what enzyme is expressed and what enzyme is not expressed to produce this
zona glomerulosa
- p450aldo expressed
- lacks 17a-hydroxylase so can't produce cortisol or androgens
33
what is the physiological affects of aldosterone (a mineralcorticoid): where is main target
- regulates Na+ and K+ in extracellular fluids
MAIN TARGET: distal tubule of kidney
1) increases active resorption of Na+
2) increases passive resorption of water (due to Na resorption)
3) increased renal excretion of K+
*** these all lead to increase in BP and blood volume
34
what is the major net effect of aldosterone (how does it do this)
to conserve body sodium
- activation of Na+ channel (Na reabsorbed, uptake from lumen)
- activation of Na/K ATPase gene
35
what are regulators of aldosterone secretion
1. concentration of K+ in extracellular fluid
- increase in K+ leads to increased aldosterone secretion (replace K for Na)
2. Angiotensin II (and ANP)
- positive regulation: angiotensin II causes vasoconstriction increasing bp (increases aldosterone)
- negative regulation: increase in atrial natriuretic peptide causes vasodialation decreasing bp
- DECREASES aldosterone secretion decreasing water and Na+ to decrease bp
36
Renin-angiotensin-aldosterone axis
- low BP/high K+ stimulates renin release from juxtaglomerular cells
- renin converts angiotensinogen to angiotensin I
- angiotensin converting enzyme (ACE) converts antiotensin I to angiotensin II
- angiotensin II binds to angiotensin II R (increase bp: vasoconstriction, aldosterone sec, increase HR, ADH secretion - upregulation of aquaporins)
37
hyperaldosteronism
- caused by adrenal tumour
- too much cortisol and aldosterone produced
- cushing-like symptoms
- too little K in circulation, too high Na and water
38
what enzyme allows aldosterone and cortisol to bind to same receptor without competition - bind to mineralcorticoid receptors
11-b-hyroxysteroid dehydrogenase
- cells that want aldosterone to bind express this
- these cells convert cortisol to cortisone (biologically inactive weak affinity)
- need this because cortisol is 100x higher in serum than aldosterone
39
what happens with chronic licorice intoxication
pseudohyperaldosteronism
- no inactivation of cortisol to cortisone in kidney
- Na and water retention, low K+. Hypertension and low renin activity (don't know why low renin...)
40
what are the two types of cells found in the testes
1. leydig cells
| 2. sertoli cells
41
testosterone/estradiol synthesis: what does 17a-hydroxylase convert
converts pregnenalone to 17a-hydroxypregnenalone
42
testosterone/estradiol synthesis: what does aromatase convert
converts testosterone to estradiol
43
testosterone/estradiol synthesis: what does 5a-reductase convert
coverts testosterone to dihydrotestosterone
44
what is the full synthetic pathway from cholesterol to estradiol/dihydrotestosterone
LOOK IN NOTEBOOK
45
hypothalamic pituitary gonado axis (testosterone axis)
GnRH (hypothalamus) --> LH (ant. pit) --> testosterone (leydig cells in testes)
46
functions of testosterone
- spermatogenesis
| - anabolic effects on enzymes in kidney muscle, liver
47
what do testosterone levels in blood depend on (3)
1. total # of leydig cells in testes
2. steroidogenic abilities of leydig cells
3. LH levels (depend on GnRH)
48
how does testosterone travel through blood?
sex hormone binding globulin
- this is synthesized in liver
- free testosterone enters cell
49
leydig cell function
- produces and secretes testosterone
| - LH has big effect on leydig cells
50
what gives leydig cells positive/negative feedback feedback
negative: estradiol and testosterone
positive: FSH!! (activin)
51
leydig cell making axis
GnRH --> LH (ant. pit) --> increase AC, cAMP --> increase steroidergenic acute regulatory protein --> stimulates testosterone transcription and release
- express GPCR
52
what receptor do sertoli cells have
FSH receptor (GPCR)
53
sertoli cell function
makes array of hormones (testosterone, DHT, estradiol)
- has array of enzymes to make these hormones
spermatogenesis
54
sertoli cell axis
FSH binds to FSH-R (GPCR) --> increase AC, cAMP --> increase androgen binding protein --> increase the [testosterone] in seminiferous tubules stimulating spermatogenesis
55
inhibin
- inhibits FSH secretion from pit
| - produced by sertoli cells in male
56
activin
- activates FSH secretion and binding
| - produces by leydig cells
57
follistatin
binds activin
| - decreases FSH synthesis!!
58
what enzyme do granulosa cells lack
17a-hydroxylase (no androgens)
59
what do granulosa cells secrete
| - what do they secrete in luteal phase?
estradiol and activin
| - in luteal phase secrete projesterone and inhibin
60
what do theca cells make
androstenediol
61
what do theca cells lack
lack aromatase so can't make estradiol
| - lack FSH-R and aromatase
62
what is needed for estrogen production
FSH
63
what does increased E2 render in the menstrual cycle
increased sensitivity of pituitary to GnRH
- initially slows it down but then it speeds up
- speed up is what causes LH surge
64
what is ovulation (and what day is it)
LH surge due to increase in E2 from the FSH production ~ day 14
65
what happens after ovulation (luteal phase)
- the corpus lueum favours production of progesterone
- GnRH pulse slows
- there is an increase in inhibin which decreases FSH
- later, higher levels of LH increase activin; increased FSH restart the cycle
66
what causes the GnRH pulses
oscillation of electrical activity in the hypothalamus
| - neural, hormonal, environmental inputs influence this
67
what increases GnRH pulses
cAMP in neurons
- negative feedback pathways may decrease cAMP levels by inhibiting AC and activating a phosphodiesterase
- this stimulation and inhibition regulate excitability of hypothalamic neurons: clock
68
where are 3 sites for calcium exchange in extracellular fluid
1. bone
2. kidney
3. intestine
69
what tells kidney to release Ca
parathyroid gland makes parathyroid hormone which tells kidney to release Ca
70
why is calcium important
1. extracellular calcium
- excitation of heart muscles
- synapse
2. intracellular calcium (10,000 more outside)
- for the use of Na+/Ca exchanger (3 na in, 1 ca out)
- important 2nd messenger
71
what does calcitonin do
reduces calcium levels in the blood
72
what does parathyroid hormone do
increase calcium levels in blood
73
what happens if parafollicular (in thyroid gland) cells are removed
- they make calcitonin
| - either no calcitonin is made or there is a tumour with excess calcitonin
74
where do you find vit. D receptors
bone, kidney, gut (initestine) also in immune cells (testes, breast)
75
what receptors do osteoblasts have
receptors for vit. D and parathyroid hormone
| - bone forming cell
76
what are osteoclasts inhibited by**
CALCITONIN
- calcitonin reduces ca in blood
- calcitonin stimulates Ca deposition in bone; stimulates osteoblasts
77
how long does the bone cycle take
6 months
- can lose bone each time if cycle is out of balance
- why it is detrimental to lose bone by breaks
78
what is parathyroid hormone inhibited by **
calcium (v sensitive)
| - parathyroid cells have ca receptor (GPCR)
79
what is stimulated by increased calcium**
parafollicular cells (make calcitonin)
80
what hormone is critical in fish
calcitonin - high ca in water
81
main effect of calcitonin
1. inhibits osteoclasts
| 2. inhibits Ca2+ absorption from gut (lowers blood ca)
82
vit. D functions
1. keep Ca and phosphorus @ normal level in blood (increases ca)
2. antiproliferation!! ~ important implications in cancer
83
what is calcitriol
active vit D
84
when is Vit. D secreted **
low Ca, low phosphorus, high PTH
85
what will happen if there is high vit. D
1. inhibit its receptor transcription
| 2. signal hydroxylase that breaks down vit. D
86
what enzyme oxidizes the vit. D precursor... where
cytochrome p450 oxidase
| - first acts on it in liver then transported to kidney where it is converted to active!!
87
where can excess vit. D be stored
liver
| - vit. D precurser oxidized in liver: this is where/how it is stored
88
what does vit. D increase the transcription of (intestine)
Ca2+ channels, calcium binding proteins, vit. D receptors
89
what affect does vit. D have on bone
stimulates bone formation and Ca2+ binding, decreases PTH
90
hyperparathyroid disease
- causes HYPERCALCEMIA
| - too much PTH... Ca2+ does not have neg feedback
91
what is used to treat hyperparathyroid disease
calcitonin
92
Rickets disease (what does this cause)
- lack of vit. D in children
- causes decreased Ca and phosphorus
- also causes rise in PTH and increased bone resorption
93
Osteomalacia Disease
- mineralization of new bone is defective - adults
- lack vit. D (low Ca or phosphate)
- associated with osteoporosis
94
vit D deficiency (2 types)
1. Type I
- due to environment or genetic effect
2. Type II
- normal vit. D levels but defect in receptor
95
what is Type II vit. D deficiency called
alopecia
96
what is Lytic Paget's disease (what do u treatwith)
- rapid bone loss
| - treat with calcitonin
97
what is Renal Secondary Hyperparathyroidism
kidney failure results in vit. D deficiency
| - decreased Ca2+ and increased PTH!!
98
what is associated with osteoporosis
low estrogen and high glucocoricoids
99
osteoporosis treatment
calcitonin, diet, exercise
100
what affect does estrogen have on bone
stimulates osteoblasts and inhibits osteoclasts (stop bone breakdown)
101
what affect does testosterone have on bone
increased (strenthens bone growth, can be converted to estrogen)
102
what affect do glucocorticoids have on bone
bone loss
103
what cells are found in the adrenal medulla
chromaffin cells
104
adrenal cortex layers
top: zona glomerulosa
middle: zona fasiculata
bottom: zona reticularis
105
what does the autonomic NS consist of
1. parasympathetic NS
2. sympathetic NS
3. enteric NS
106
sympathetic NS pathway
brain --> pre-ganglia --> post-ganglia --> secretes norepinephrine --> innervates adrenal medulla --> AM secretes epinephrine
107
where does epinephrine bind**
a1 or a2/b adrenergic receptor
108
what type of receptor is the a1 adrenergic receptor
GPCR (Gaq)
109
what type of receptor is the a2 adrenergic receptor
GPCR (Gai)
110
what type of receptor is the b adrenergic receptor
GPCR (Gas)
111
what stimulates the secretion of norepinephrine and epinephrine from the adrenal medulla (and what receptor does it use)
ACh
| - nicotinic R
112
what % is serum norepinephrine and what is it due to?
10-20%
| - due to nerve leakage
113
what is the catecholamine synthesis pathways
tyrosine --> (tyrosine hydroxylase) --> DOPA --> dopamine --> norepinephrine --> epinephrine
114
what reaction occurs for norepinephrine to epinephrine (and what enzyme is used)
- methylation (adds methyl group to norepinephrine)
| - enzyme: phenylethanolamine-N-methyltransferase)
115
what reaction occurs from DOPA to dopamine and what enzyme
- decarboxylation
| - DOPA dexarboxylase
116
what hormone is stored and readily releasable in the adrenal medulla
epinephrine
117
what is sexual differentiation driven by* *
presence or lack of androgens
118
what does SRY do
protein that initiates the testes in males
119
what protein initiates the wolffian ducts
anti-mullerian hormone
| - wolffian ducts in males!
120
what are the ducts that females have
mullerian ducts
- form the uterus, fallopian tubes, upper part of vag
- form from urogenital ridge
- default if no androgen exposure
121
what do wolffian ducts form
form epididymis, vas deferens, seminal vesicles
122
what is critical for development of wolffian ducts
have to be exposed to testosterone before embyrogenesis and development
123
what is the anti-mullerian hormone produced by
leydig and sertoli cells
| - controls the stabilization of wolffian ducts
124
what comes first: ovarian or testicular development
testicular
| - because leydig cells form first
125
what are 4 conditions associated with amenorrhea
1. GnRH deficiency (Kallman's Syndrome)
2. Functional Hypothalamic amenorrhea
3. Hyperprolactemia
4. Menopause
126
what is Kallman's syndrome
- no migration of GnRH producing cells or olfactory neurons to the hypothalamus
- no sexual maturity or smell
- GnRH deficiency
127
what is functional hypothalamic amenorrhea
- low pulsatile GnRH release
128
what is associated with functional hypothalamic amenorrhea
low FSH, LH and leptin
129
hyperprolactemia (why does it happen)
dopamine is not inhibiting prolactin release
130
why does menopause happen
ovary stops functioning (avg. age 52)
131
what are 6 examples of intersex
1. kleinfelter's syndrome
2. turner's syndrome
3. male hypogonadism
4. intersex 46 XX (female pseudohermaphroditism)
5. intersex 46 XY (male pseudohermphroditism)
6. androgen insensitivity syndrome (46 XY)
132
kleinfelter's syndrome: code, symptoms
male 47 XXY (mostly male.. depends on androgen:estrogen ratio)
- gonadal dysgenesis
- low testosterone and androgens
- mental retardation: rare
- 1/500
133
turner's syndrome: code, symptoms
female 45 X
- almost no estrogen or progesterone
- no secondary sex characteristics
- developmental probs (hearing/kidney function)
- fetus usually dies 1/5000
134
male hypogonadism
```
female characteristics (developmental default = female)
- lack ability to respond to androgens
```
135
Intersex 46 XX: appearance and causes (3)
female pseudohermaphroditism
- when females with 2 X chromosomes have male phenotype appearance
1. 21a-hydroxylase deficiency
- makes androgens... increased testosterone and masculinization
2. aromatase deficiency
- lack of estrogen
3. increased androgen exposure in utero
136
what happens if there is androgen exposure @ 12 weeks
both penis and ovaries
137
Intersex 46 XY: causes (3)
Male pseudohermaphroditism
- all androgen biosynthetic dysfunctions
1. LH receptor mutation (or SR-1 mutation)
- decreased androgen (testosterone) production
- hypogonadism
2. 17a-hydroxylase deficiency
- can't make androgens (testosterone). have ambiguous gonads or femitization
3. 5a-reductase deficiency
- converts testosterone to DHT
138
androgen insensitivity syndrome
- testes present but absent wolffian ducts. Female appearing genetalia
- testosterone doesn't bind to androgen receptor as it does normally
- androgen receptor mutation common!!
- female secondary sex characteristics but no menarche
139
what is the difference in melatonin lvls between rotating night shift workers and day shift workers
1. later acrophase (peak time)
2. lower peak amplitude
- - these changes in melatonin lvls may be related to change in sex hormones
140
what were the 2 models adjusted for
1. model 1
- smoking
- age
- BMI
2. model 2
- other sex hormones
- menstrual phase and menopausal status
141
what were results
- higher estradiol and progesterone in all groups working rotating shift work
- highest lvls of estradiol = pre-menopausal women
- lower testosterone
- no change in cortisol
- rise in DHEA in women in their follicular phase!!! (other women not significant)
142
why is level of DHEA important in this shift-worker paper
because this means more androgens that can get converted into estrogen
143
where are glucagon receptors found
- liver
| - kidney
144
where are insulin receptors found
everywhere
145
what do delta cells in pancreas secrete
somatostatin
146
what cells does insulin activate/inhibit
activates b-cells and inhibits a-cells
147
what cells does glucagon activate/inhibit
activate all (b, a, d cells)
148
what does b-cells secrete
insulin
149
what are proteins that amplify insulin's effects called (and where are they released from)
incretins
| - released from small intestine
150
2 incretins that are released from the small intestine
- incretins amplify insulins effects!!
1. Glucagon-like peptide 1 (GLP-1)
2. Gastric Inhibitory Peptide
151
what does glucagon-like peptide 1 do
- acts on the pancreas: stimulates insulin transcription and release
- decreases secretion of glucagon
- slows gut emptying; increasing absorption
152
what do we use to make insulin
recombinant DNA technology (genetic recombination)
153
how is insulin synthesis regulated
stimulated by insulin at RECEPTOR TYROSINE KINASE
| - GLUCOSE SENSOR
154
how is insulin secreted
- insulin takes oven 1 hr to make so it is stored
- secretion stimulated by glucagon-like peptide 1 acting on GPCR
- also influx of Ca
155
what are 3 hormones that use receptor tyrosine kinase
1. IGF-1 (insulin-like growth factor 1)
- negative feedback on GH
2. IGF-2 (insulin-like growth factor 2)
- fetal growth
3. insulin
156
How does the insulin receptor tyrosine kinase function?
1. signal complex (add phosphate to substrates that recruit proteins)
2. phosphorylation cascades
157
how does evolution occur
gene duplication (split a gene and change it without mutation occurring)
158
insulin effects (5)
1. metabolic
2. cell growth
3. fetal growth
4. suppresses glucagon transcription
5. brain function
159
what are the 2 pathways of insulin signaling
1. mitogenic (growth via MAPK)
2. metabolic (after a meal via PI3K/PKB)
- sometimes cell will do both
160
what do SH2 domains recognize
phosphorylated tyrosines
161
what do SH3 domains recognize
proline rich sequences
162
what binds to the tyrosine kinase receptor and acts as a dock for other proteins
IRS - insulin receptor substrate
163
what degrades insulin receptors (downregulated)
gets internalized, insulinases degrade
164
what is leprechaunism
- defective insulin receptor
- some mutations lead to less severe phenotype: insulin resistance
- heterozygous mutations v. severe (elf)
- heterozygous: free of disease but some ppl w leprechaunsim will carry another mutation of insulin gene and show symptoms
165
difference in symptoms between type 1 and 2 diabetes
1: weight loss, never asymptomatic
| 2. no weight loss (obese), often asymptomatic
166
what are 3 requirements for type 1 diabetes *
1) b-cell reactive T-cells must be activated
2) the responses need to be proinflammatory
3) the regulation of autoreactive responses must fail
167
type 2 cases - 2 cases with extreme insulin resistance
1. leprechaunism (receptor defected)
| 2. when there is an antibody against a receptor
168
type 2 diabetes is due to
hyperinsulinism
- receptor insenstive because of this
- signal pathway is defective
169
what replaces the b-cells in type 2 diabetes
amylase deposits
170
what are 4 treatments for type 2 diabetes
1. diet/exercise
2. drugs that lower glucose production in liver
3. drugs that stimulate insulin secretion (hypoglycemia major side effect)
4. drugs that affect glucose absorption in small intestine (glucagon-like peptide 1) ... (increase insulin synth and secretion, dec glucagon sec)
171
what is lipogenesis
when u eat sugar store fat
| - can get sugar tolerance on high fat low carb diet
172
what happens to GLUT1 with hyper and hypoglycemic
- hypoglycemic: upregulation of GLUT1 so brain gets the glucose it needs
- hyperglycemic: downregulation of GLUT1
173
what is in the humoral immune system
mediated by b-cells (produce antibodies against a specific antigen)
- antigens that are freely circulating or OUTSIDE infected cells
174
what is the cellular immune system
mediated by T cells
- INSIDE infected cells
- contains antigen presenting cells
175
what do antigen presenting cells do and what do they express
break down proteins on the antigen presented to it
- the molecules on the antigen presenting cells that present the antigen are called "major histocompatibility complexes (MHC)"
176
where are T cells produced
thymus
177
what are the 2 different types of T cells (and what do they do)
1. cytotoxic T cells
- kill infected cells
2. helper T cells
- help other cells in the immune system
178
where are potentially dangerous T and B cells eliminated
thymus and bone marrow
179
where are MHC class II and I receptors found
- MHC class II receptors found on antigen presenting cells
| - MHC class I found on all other cells
180
what are the 4 steps for antigen recognition by T cells
1. Antigen uptake (APC)
2. Antigen presentation
3. T cell activation
4. T cell inactivation
181
what happens in step 3: T cell activation
second signal provided by CD80/86-CD28 (CD28 is on T cells)
- this induces the expression of CD 154 and later CD152
- CD154 binds to CD40 on APC
- these APC-T cell interaction causes the proliferation of downstream T cells
182
what happens in step 4: T cell inactivation
- CD152 (expressed 48-72 hours after T cell activation) will bind to CD80/86 on antigen presenting cells because of its higher affinity
- this replaces CD28 and initiates T cell activity/death
183
SUMMARY: what 2 signals are required for (both TH and TC cells to activate)
1. the TCR expressed antigen specific receptor binds to the MHC compex
2. CD28 (on T cell) binds to CD80/86 on APC: leads to T cell proliferation
184
autoimmunity is ________
multifactorial
185
what are 5 possible disruptors of self tolerance (5)** multifactorial
1. defects in apoptosis-related molecules
2. defects of CD152 on T cells may prevent apoptosis of autoreactive T cells
3. defects in B cell tolerance
4. defects of regulatory T cells ***
5. hypocortisolism (may underlie pathology behind inflammation, pain, fatigue)
- both environmental and genetic factors involved
186
Central T cell tolerance in the thymus (5 steps)
1. pre T cells rearrange their T cell receptor
2. unproductive (non functional) rearrangements lead to apoptosis
3. productive (functional) are then tested for antigen recognition
4. apoptosis for cells based on their 'too high' or 'no avidity'
5. surviving low-avidity cells reach periphery of CD4 or CD8 cells
187
what are three environmental factors involved in autoimmune disease
1. toxins
2. diet
3. infectious agents
188
what virus are babies that develop type 1 diabetes commonly exposed to?
Rubella virus (toxin)
- b-cell proteins share a similar molecular structure as proteins in the rubella virus
- b-cells become attacked
189
what does 21a-hydroxylase do
involved with the biosythesis of steroid hormone aldosterone and cortisol
190
what is associated with Addison's disease
21a-hydroxylase (a cytochrome p450 enzyme involved with the production of cortisol and aldosterone)
- Addison's: hypocortisolism
191
circadian rhythm and T cells
- cortisol controls # of T cells by inducing their apoptosis
- negative cross correlations between cortisol levels and lymphosubtypes
- CIRCADIAN RHYTHM OF CORTISOL LOWERS T CELLS
192
what nerve sends signals from liver to the brain
vagus nerve to the nucleus tract of solaris
193
what do visceral adipose cells produce a significant amount of
proinflammatory cytokines
| - disrupt normal insulin action leading to insulin resistance
194
what area of brain do adiposity signals reach and how
reach arcuate nucleus which go to hypothalamus
| - through circulation!!
195
where does the hypothalamus receive signals from
nucleus tract of solaris and arcuate nucleus
| - hypothalamus receives orexigenic nt and anorexigenic nt
196
2 orexigenic nt
NPY and agouti related peptide neurons
197
2 anorexigenic nt
- POMC and CART (cocaine-and amphetamine related transcript)
- inhibit appetite by CCK
198
what are 3 satiety signals from the GI tract
1. PYY
2. Glucagon-like peptide-1 (GLP-1)
3. cholecytokinin
199
what is PYY secreted by
L cells (decrease food intake)
200
what is the agonist to GLP-1
extendin 4 (decrease food intake)
201
what does leptin do
- decreases food intake and increases metabolic rate
- inhibits NPY and AgRP neurons
- stimulates POMC and CART neurons
202
what hormone is produced in adipose tissue
leptin
| - not satiating signal; an adiposity signal
203
where is the leptin receptor found (and what kind of receptor is it)
arcuate nucleus
| - cytokine-R, signals through STAT3
204
what happens to mouse with a mutation in the production of leptin or leptin receptor
causes obesity
205
what does ghrelin do
stimulates hunger (adiposity signal)
206
what neurons does ghrelin stimulate
- stimulate NPY, and AgRP
| - inhibits POMC
207
what hormone does ghrelin stimulate the release of
growth hormone
208
what glands produce ghrelin
oxyntic glands of stomach
209
what receptor does ghrelin bind to
Growth hormone secretagogue receptor
210
what are 6 cytokines that are produced by adipose tissue
1. leptin
2. adiponectin
3. adipocytokines
4. resistin
5. estradiol
6. angiotensinogen
211
what does leptin do (in addition to appetite regulation)
DECREASES INSULIN SENSITIVITY. decrease insulin secretion
- decreases intracellular lipid in muscle
- regulation of bone absorption... heavvier = increased risk of osteoporosis
212
what does adiponectin do
INCREASE INSULIN SENSITIVITY
- anti inflammatory
- inverse correlations to BMI
213
what does adipocytokines do
DECREASE INSULIN SENSITIVITY.
| PROINFLAMMATORY
214
what does resistin do
decreases insulin sensitivity
215
what does angiotensinogen do
regulates BP and fluid balance
216
factors affecting weight gain
1) behaviou (diet/exercise)
2) genetics
3) age
217
what hormones act on the vagus nerve
cholecytokine, GLP-1, PYY
218
2 pathways for light
1. retinohypothalamic path - circadian rhythm and endocrine functions
2. primary optic tract - visual perception and responses
219
what protein does light signal through
melanopsin
220
what cells receive light
retinal ganglion cells
221
health problems associated with circadian clock dysregulation
1. cancer
2. obesity
3. insomnia
222
what are hormones relating to breast cancer and the hypothamus' exposure to light
1. serotonin
2. melatonin
3. vitamin D
4. GnRH
5. estrogen
6. progesterone
223
what is exposure to night at light associated with
breast and prostate cancer
224
what is melatonin a regulator of
ERa (estrogen receptor alpha)
| - clear relationship to breast cancer
225
what is the rate limiting step of serotonin synthesis
serotonin --> acetylserotonin
226
what does serotonin and melatonin start out as in their synthetic pathway
tryptophan
227
what does melatonin do to the estrogen response pathway
inhibits it by binding to the MT-1-R
228
where is serotonin synthesized
in gut. rest is made in CNS
| - highest serotonin levels in mid afternoon
229
what does vit. D have important implications for
CANCER (antiproliferation)
230
what does vit. D do (antiproliferation role) ****
- inhibits COX2 - cyclooxygenase 2 (important for prostaglandin synth)
- inhibits estrogen receptor alpha... thus diminishing signal for proliferation
- decreases the expression of aromatase (less estrogen)
- induces expression of apoptotic cell death proteins (Bax and Bak) and cell cycle arrest proteins
231
when does vit. D peak and where is it produced
after mid-day
| - produced in liver
232
what disorder do 25% of people with breast cancer have
seasonal affective disorder (SAD)
233
what gene does vit. D activate the transcription of?
- the initial serotonin synthesizing gene
| - tryptophan hydroxylase
234
what 2 hormones downregulate estrogen signaling
melatonin and vit. D!!
235
2 hormones that decrease occur with age
low dehydroepiandosterone (DHEA) and testosterone
236
is replacement testosterone safe? why or why not
no
- increased blood clots
- increased risk of heart attack
- stroke
- heart-rhythm irregularities
237
what are the functions of estrogen and progesterone
- maintain reproductive function
| - anti-absorptive effects on bone
238
what happens after menopause
- risk for osteoporosis
- risk for coronary heart disease
- stroke and dementia
-- is this related to E and P??? that decrease with age
239
what happened in the estrogen replacement studies
- reduced coronary heart disease by 50%
- reduced osteoporosis
- but increased in stroke slightly.... therefore they stopped
240
what happened in the estrogen/progesterone replacement studies?
- saw increase in breast cancer
- saw increase in coronary heart disease and stroke
- reduction in colon cancers and fractures but risk outweighed the benefits... eventually stopped
241
what demographic are estrogen replacement therapies beneficial
women with a hysterectomy, taking E a few years close to menopause... safe and may reduce breast cancer relief.
242
what wavelength of light is needed to make serotonin and vit. D
serotonin = 480 nm
| vit. D = 295 nm
243
where is ERa expressed
reproductive tissues and mediates majority of sexually dimorphic and reproductive functions
244
where is ERb expressed
diverse patterns of expression: expression in prostate, brain and immune
245
what is the function of the C domain on the estrogen receptor
DNA binding, dimerization
246
what is the function of the E domain on the estrogen receptor
ligand binding, dimerization
247
what is tamoxifen
ANTAGONIST of the estrogen receptor in breast tissue
248
what happens in the classical nuclear action (nuclear initiated steroid signaling)
activation of target gene by E2/ER OR no action by antagonist tamoxifen/ER
249
what happens in non-classical nuclear action (non-genomic)
- mediated through GPCR
- phosphorylated estrogen receptor is v active
- ER regulates the transcription of genes without a HRE
250
what is E2 signaling via
GPCR30
