Lecture 11 to post [Compatibility Mode]

Lecture 11 to post [Compatibility Mode] - Lecture Lecture...

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Lecture 11 overview In vivo aspects of the DNA damage response the beginning of life: development in utero exposure development, th t ili ht rs: the twilight years: aging and senescence
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The contribution of cell lineage to DNA d i i DNA damage response in vivo Gastrointestinal (GI) tract damage by chemotherapy or radiation -postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome -above 8Gy, dose-dependent stem cell death leads to decreased crypt regeneration, the level insufficient to rescue GI mucosa
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The contribution of cell lineage to DNA damage response in vivo microvascular endothelial apoptosis after 15Gy: faster onset of apoptosis in lamina propria compared to columnar epithelia (TUNEL assay:apoptotic nuclei brown, normal nuclei blue; or FITC-labeled annexin V, apoptotic cells stain green and normal cells stain red) … there is a threshold for massive endothelial apoptosis the red TUNEL positive nuclei are present on cells that stain blue (positive for CD31: endothelial lineage marker)
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DNA damage: impact on gametes xenobiotics and other environmental factors can act directly on male germ cells within mature testis -effective cellular proofreading in stem cells that produce sperm -however, mature sperm lose capacity to respond to DNA damage (no cytoplasm) -sperm believed to be much more susceptible to damage than the egg because of its prolonged solitary existence and relative lack of protective, repair and self destruct mechanisms
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DNA damage response in d l t development teratogenesis and mutagenesis are two primary processes for introducing birth defects mutagenesis involves the production of heritable changes in genetic material and ultimately involves alterations in either the primary sequence of specific target DNA teratogens cause noninherited malformations, inducing congenital defects by altering fundamental embryological processes, may be linked to alterations in gene function or interference with signal transmission during development The scope: 40-75% of fertilized ova in humans are wasted –early spontaneous b ti t ib t t h lf th l ( ith h l abortion contribute to half these loses (many with chromosomal aberrations) ~3% of liveborn infants have malformation apparent at birth, half of these are of unknown etiology and 20% caused by chromosomal aberration or gene mutation
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DNA repair and development exposure in utero to DNA damaging agents can cause birth defects
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DNA repair and development Disruption of the DNA damage response impacts developmental outcome
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Cell lineage and development impact DNA damage response in vivo DNA damage and development of the central nervous system: ‘cellular proofreading’: AT characterized by progressive neurodegeneration ATM appears to act as developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage
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The contribution of cell lineage to DNA d i i DNA damage response in vivo Atm-dependent apoptosis coincides with p53 stabilization
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