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Ординатура / Офтальмология / Английские материалы / Retinal Degeneration Disease_Hollyfield, Anderson, LaVail_1999

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INDEX

553

Phototherapy (PDT), 297-301, 299f, 310-313 damage from, 406-414

Phototransduction cascade, 505-506 Phototransduction proteins, 413

Pigment epithelium-derived growth factor (PEDF), 513-517

for neuroprotection, 292-294

and VEGF synthesis in hRPE cells, 515f-516f

Pigment/pigmentation, retinal, 101-106 depigmented patches on RPE, 96f regeneration of, 101-106

on retina, 3-7

rhodopsin. See Rhodopsin

See also Retinitis pigmentosa (RP) Plasmids, 268-269, 363

Polymerase chain reaction (PCR)

with occludin and ZO-1 labelling, 181-182 quantitative reverse transcriptase (QRT-

PCR), 259-261 real time, 235-236

semi-quantitative RT, 148-150, 174 POS. See Photoreceptor outer segments

(POSs)

Posterior pole atrophy, 58f Prenylation, 92

Primer sequences, 359t

Promotors, tissue/cell-specific, 204-206, 267-273

Protein kinases

A (PKA), 205, 328, 330-331 C (PKC), 328, 330-331

Protein misfolding, 82, 85-86, 103-104 Protein synthesis inhibition, 457-458 Putrescine, 70-71

Q

Quantitative reverse transcriptase (QRTPCR), 259-260

R

Rab escort protein (REP-1), 57, 59 Rat retina. See under Animal models RCCI-like domain (RLD), 29-32, 30f

RDHs. See Retinol dehydrogenases (RDHs) Reactive oxygen species, 291

Receptors

avb5 integrin, 120-121, 500-501 Mer tyrosine kinase (MerTK), 120,

499-502 scavenger CD36, 120

Recoverin, 379-380, 413

Regulator of chromatin condensation (RCCI), 29-32

Retina

acidification of, 414, 439, 444 AIPL1 expression in, 90-93, 472-473

caspase-3 activity in, 334, 365, 449-450, 531

crystal deposits on, 49-52

degeneration of. See Retinal degeneration development of, 90-93

differences between species, 377-378 exposed to space environment, 419-423 function of, 519-523

NUB1 expression in, 472-473 phototherapy damage to, 297-301 pigmentation on, 3-7, 96f, 101-106 pure-cone type, 137

regeneration of, 377-378 RS1 role in, 284-288

supramolecular Usher protein complexes in, 349-352

thickness defined, 164, 166 Usher 1 proteins in, 341-347 VEGF overexpression in, 179-184

See also specific retina structures

Retinal

9-cis type, 105

11-cis, 125, 505

all-trans-retinal, 70, 465-467, 466f, 505 Retinal degeneration

age-related/late-onset, 41-47 animal models of, 79-228 assessment of progression, 169-172

basic underlying science of, 455-538 and bHLH transcription factors, 155-160 causes of, 417

cytokine-induced, 275-280

diagnostic, clinical, cytopathological, and physiologic aspects of, 55-78, 169

and docosa-hexaenoeic acid (DHA), 536-537

gene therapy and neuroprotection for, 231-337

and hypoglycemia, 170-172 induced, 405-450

inflammation/inflammatory mediators and, 275-280

LIF expression and, 150-151

molecular genetics and candidate genes in, 3-52

554

INDEX

and oxidative stress, 535-536 phases of, 405

process of, 405-409

in space flight environments, 417-423 stem cell repair of, 381-386

and survival signalling, 531-538 in Usher syndrome, 341-352

Retinal detachment, 163, 167t, 196 Retinal ganglion cells (RGCs)

death of, 397, 399, 401, 449-450 Dil-labelled, 399-400

function of, 389 injury-induced loss of, 447-450 and neurotrophins, 447-449 remodelling in, 397-401

survival after injury (crush) to, 333-337 Retinal perfusion, 188-192

Retinal pigment epithelium (RPE) amino-retinoid compounds in, 69-73 animal model mutations for, 95-99, 180 apical microvilli of, 519-523

apoptosis of cells in, 363-366 atrophy of, 49, 57-60

culture of, 357-358 differentiation of, 359-360

dysfunction and death of, 41-42, 364, 365f exposed to space environment, 419-423 function of, 499, 532

human (hRPE), 513-517 inflammatory processes and, 537 lipofuscin in (RPE LF), 63-67, 72-73 neural differentiation of, 357-360

as outer blood-retinal barrier, 179 phagocytosis in, 97, 119-122, 499-502 phototherapy damage to, 297-301 pigment regeneration in, 101-106 retinoid-processing proteins in, 480-481 specific promoter for, 247-252

suitable for transplantation, 366 support of photoreceptors, 95 survival signalling in, 531-538 targeting of, 267-273

tight junction (TJ) proteins in, 179-184 vacuoles in, 96, 98f, 112-113

Retinal stem cells (RSCs), 210, 377-380 Retinal transplantation, 367-374

of fetal retinal sheets, 372-374 mechanical support for, 373-374 pretesting for, 369

procedure for, 369, 373 results of, 369-372

trophic effects and permanence of, 373 visual responses after, 370-372

Retinal vein occlusions, 187, 310-313 Retinal vessel attenuation, 96-97 Retinitis pigmentosa (RP)

autosomal dominant. See Autosomal dominant retinitis pigmentosa (adRP)

and C214S, 142-143 clinical flowchart of, 17f defined, 133

and EBP50, 521

GTPase Regulator (RPGR), 29-32 and L185P/Rom-1, 142-143

and macular edema, 309-313 night blindness in, 4

onset times of, 349 and P216L, 142-143

pathogenesis of, 142-143, 349, 351 and peripherin/rds mutations, 141-142 prevalence of, 377

TA injection for, 310-313 treatment of, 147

X-linked (XLRP) mutations in, 29-32 Retinoblastoma (Rb) protein, 214,

219-222 Retinoids

binding properties of, 466-469 transport and metabolism of, 465-469,

507f

Retinol dehydrogenases (RDHs) function of Rdh11, 505-509, 506t interaction with CRALBP, 479-480 Rdh12 expression on, 507-508 RetSDR1 and prRDH, 508

SDR family of, 506-507 Retinopathy of prematurity (ROP), 425 Retinoschisis (RS)

disease mechanisms in, 283-285 gene therapy for, 285-288

Retinyl ester, 101

RGC. See Retinal ganglion cells (RGCs) Rhodopsin, 102-106

and autosomal dominant RP (ADRP), 233-238

formation of, 125-130 GRK1 inactivation of, 138 isorhodopsin, 105

levels of, 413

light-activated phosphorhodopsin (R*P), 459-460

misrouting of, 405

INDEX

555

P23H

design and screening with, 234-235 long-term suppression of, 236-238 siRNA effects on, 235-236

rhodopsin kinase (GRK1), 488-489 RhoGDI, 487-488

Rhodopsin mutations, 81, 86 RNA (ribonucleic acid)

induced silencing complex (RISC) of, 233, 305-306

interference (RNAi), 233-238, 305-306 mitochondrial (mRNA), 205, 358-359, 401 short-interfering (siRNA), 233-238,

527-528

RO.8 promotor, 248-249, 251

ROAI. See Autosomal recessive optic atrophy (ROA1)

Rod-dependent cone viability factor (RdCVF), 316-318

Rod-derived cone viability factor (RdCVF), 10 Rod inner segments (RIS), 128f, 130, 455,

459

Rod outer segments (ROS) detergent-resistant membrane rafts of,

491-495 development of, 126-128 disrupted structure of, 145 function of, 455, 459

microvilli ensheathing of, 519 phagocytosis of, 69 shortened, 489

tyrosine phosphorylation of, 492-495 Rods

arrestin translocation in, 455-463, 458f CAIs effect on, 441-445 cGMP-phosphodiesterase b-subunit gene

in, 217-228

cone survival and, 434 defined, 133

degeneration of, 90-91, 93, 105, 141-145 EGFP in, 204-205

function and loss of, 133

hyperoxic effects on, 427f, 428, 431, 434 light flash response of, 83-84 photosensitivity of, 102-103

pigment regeneration in, 101-106 rapid loss of, 368

rod a-waves, 159 rod-cone dystrophy, 10

sensitivity depression in, 125-130 See also Cones; Photoreceptors

ROS. See Rod outer segments (ROS) Royal College of Surgeons (RCS) rat, 95,

321-325, 368, 500

RP. See Retinitis Pigmentosa (RP)

R*P (light-activated phosphorhodopsin), 459-460

RPE. See Retinal pigment epithelium (RPE) RPE65 proteins

as cell markers, 379-380 defined, 240

See also Genes

RS. See Retinoschisis (RS) RS1 protein (retinoschisin)

characteristics of, 283-284

structure and disease mechanisms of, 284-285

S

SCs. See Stem cells (SCs) SDS-polyacrylamide gel electrophoresis

(PAGE), 44-47 Serotonin, 70-71

Short chain dehydrogenase/reductases (SDR), 506-507

Short interfering RNA (siRNA), 233-238, 234-235

Signal peptides, 284

Signal transducers and activators of transcription (STAT) pathway, 277-279

Sodium bicarbonate transporter (NBC3), 350 Space flight environments

ionizing nuclei and cosmic rays, 422 microgravity, solar radiation, and O2

fluctuations in, 423 orbital data of, 418

retinal degeneration in, 417-423 Sprague-Dawley rats in, 418-423

Spermine/spermidine, 70-71 Sprague-Dawley rats, 418-423 Staining. See Labelling and staining Stargardt disease (STGD)

and all-trans retinal, 465-467, 469 genetic factors in, 10-13, 63

STAT pathway, 277-279 Stem cells (SCs)

bone marrow-derived (MSCs), 384-386 brain-derived, 384

characteristics of, 377-380 controversy over use, 382-384 defined, 381-382

556

differentiation of, 382

embryonic. See Embryonic stem (ES) cells

neural (NSCs), 210-211

retinal (RSCs), 210, 377-380, 383 for retinal repair, 381-386

STGD. See Stargardt disease (STGD) Subretinal implantation, 321-325 Subretinal space

GFP expression in, 250f hemorrhage in, 196

histological neovascularization in, 190, 191f

injected with rAAV, 267-273 membranous whorls in, 97 retinal implants in, 321-325 “ubiquitous” promoters in, 264

Sucrose gradient sedimentation, 43, 45 Superior colliculus (SC), 369-372,

447-449

Suppressors of cytokine signaling (SOCS), 275-280

Survival signalling, 531-538 Synaptic terminals

localization of, 346-347

and neural activity, 351, 352f, 392-393 remodelling of, 406-407

Syntaxin, 379-380

T

Targeted gene replacement (TR), 111-114 Tectum, 389-393 Tetramers/tetramerization, 143 TFIIB-TBP binding complex, 221, 223 Threshold measurements, 170-171 Thrombi/emboli, 187

Thyroid hormone receptor beta 2 (TRb2), 150-151

Tight junction (TJ) proteins, 179-184 Tol2 transposase based systems, 203-204

Topography/topographic maps (retinotectal) construction of, 390-391

in lizard models, 392-394 restoration of, 389-394, 391-393 upregulation in, 391-392

Toxicity, retinal, 63-67, 69-72, 291-294, 425-435

Transcription factors

and b-PDE promoter, 218-228

Beta2/NeuroD, 155-160

bHLH (basic helix loop helix), 155-160

INDEX

Bmi1 repressor, 209-214, 210f

CRX (cone-rod homeobox), 150-151 GAL4, 268-270, 272-273

gene regulation by, 217-228 Nr2e3 (nuclear receptor), 151

NRL (neural retina leucine), 133-138, 148, 150-151

Sp1, Sp3, and Sp4, 218-219, 223-225, 227

Transducin, 413

Transducin alpha subunit (Ta), 125-126, 129f

Transgene expression, 125-126, 249 Transgene manipulation, 188 Transgenesis/transgenetic technology,

201-206

limitations and future of, 205-206 in zebrafish, 202-203

Transglutaminase, neural (TGN), 525-529 antiserum production, 525-526

and optic nerve regeneration, 529 Transplantation

of BDNF, 363-366 pretesting for, 369 safety of, 385-386 timing of, 382-383

See also Retinal transplantation; Stem cells (SCs)

Triamcinolone acetonide (TA), 309-313 procedure for injection, 311

Trophic factors, 373 Tryptamine, 70-71

TUJI. See Neuron-specific b-tubulin III isoform (TUJI)

TUNEL (terminal deoxynucleotidyl transferase UTP nick end labelling) technique, 426-433, 449-450

quantification of, 427-428 Two-alternative forced choice (TAFC)

protocol, 169-172 Tyramine, 70-71 Tyrosine, 492-495

U

Ultraviolet (UV) spectrum, 71-72 Uncoupling protein UCP2, 291-292 Unfolded protein response (UPR), 85-86 Upregulation

of FGF2, GFAP, and c-Jun expression, 427, 431-432

in optic nerve, 525-529

INDEX

557

in topographic maps (retinotectal),

Vision

391-392

assessment in mice, 169-172

USH proteins

central, 196, 283

molecular analysis of, 349-352

color vision, 23f, 439

supramolecular complexes of, 350-351,

night blindness (nyctalopia), 4, 23, 49

352f

peripheral, 283

and Usher syndrome, 346

sudden loss of, 196

Usher syndrome (USH), 341-347, 349

Visual acuity

 

after TA injection, 312f

V

measurement of, 170-172, 171f

Vacuoles in RPE, 96, 98f, 112-113

Visual cycle physiology, 47, 481

Vascular endothelial growth factor (VEGF)

Visual evoked response (VER), 24f

controlling expression of, 303-306

Visual fields, 23f

and hypoxia, 163-164, 167, 198-199

Vitreous

and neovascularization, 180-184

hemorrhage into, 196

retinal overexpression of, 187-192

See also Intravitreal injections

synthesis inhibition in, 513-517

 

tight junction (TJ) proteins in, 182-184

W

Vasoproliferative retinopathy, 187-192

Western blot of RPE65 expression, 250f

Vector titers, 258-261

 

VEGF. See Vascular endothelial growth factor

X

(VEGF)

X-linked retinitis pigmentosa (XLRP), 29-32

Vein occlusions, 187, 310-313

Xenopus laevis, 141-145, 219-222, 456-457

Veins. See specific veins

 

VER (visual evoked response), 24f

Z

Verteporfin (Visudyne), 36, 297-301

Zebrafish (Danio rerio) retina, 201-206

Vimentin, 379-380

ZO-1 labelling, 181-184

Figure 9.3. Ocular coherence tomography (OCT) through the optic nerve (arrowheads) and macula of the right eye shows an abrupt demarcation (asterisk) between the island of intact retina and the area of atrophy. The outer retina and RPE are absent, but a thin layer of inner retina and Bruch’s membrane (arrows) are intact within the area of atrophy, consistent with histopathological samples from other patients with choroideremia (Compare to Figure 9.4). Increased signal from the choroid underlying the atrophic area could be consistent with fibrosis of the choroid.

Figure 9.4. Histopathology of choroideremia in a specimen taken from another patient. There is fibrosis of the choroid and only a single choroidal artery remains. The retinal pigment epithelium and outer nuclear layers are absent. The inner nuclear layer rests against Bruch’s membrane. H&E ¥330. Reprinted from: Spencer WH, Ophthalmic Pathology, An Atlas and Textbook (CD-ROM), Figure 9-723, 1997, with permission from Elsevier.

Figure 36.3. Flourescent fundus image showing widespread GFP expression in rat retina 1 week after subretinal injection of 3 mL VSV-CbA-GFP lentiviral vector (A). Fundus image of same rat under white light illumination

(B). Arrows indicate small hemorrhage resulting from subretinal injection. Both images acquired with a Retcam II imaging system (Massie Research, Pleasanton, CA).

Figure 36.4. High magnification view of GFP positive photoreceptors of mouse retina injected subretinally with VSV-CMV-GFP LV vector at age P7 (A). Lower magnification view (B) of the same retina shown in (A) where RPE and photoreceptors are seen expressing GFP. Expression of GFP restricted to the RPE layer in P14 mouse retina injected with VSV-CMV-GFP LV vector (C). Injection track mark shown (arrows) and evidence of immune response from autoflourescent macrophages bordering track mark (D). Low magnification view showing extent of GFP expression along entire length of the RPE (E).

Figure 41.2. Multifocal ERG performed 1 week after PDT demonstrates reduced local retinal function in areas of PDT-treated retina. (A) Averaged responses from 6 normal rat eyes shown topographically demonstrate slightly reduced retinal function at the location of the optic disk (white circle). (B) Responses are reduced centrally in the PDT-treated area of an eye treated with PBS 2 days prior to PDT. (C) The contralateral, BDNF-treated eye shows improved retinal function in the PDT-treated area. (D) Superimposed multifocal ERG responses from the eyes shown in (B) (black traces) and (C) (red traces) show improved function centrally in the BDNF-treated eye. Reproduced with permission of Investigative Ophthalmology and Visual Science in the format Other Book via Copyright Clearance Center from Paskowitz et al., Invest Ophthalmol Vis Sci 2004;45:4190-4196.

Making a map – a two step process

1. Coarse map: activity-independent mechanisms

molecular guidance cues

retina

tectum

2. Refinement: activity-dependent mechanisms

Nasal

Temporal

Rostral

Caudal

Figure 55.1. Diagram of two overlapping phases involved in restoration of retinotectal topography. During the activity-independent phase (left panel), RGC axons (dots in retinal outline) project axons with wide-spread terminal arbors in the optic tectum (jagged shapes in tectal outline). In the second phase, activity-dependent mechanisms focus terminal arbors and produce precise topography.

Figure 55.2. Visual training restores topography. Top panel: retinotectal maps assessed electrophysiologically. Numbers in tectal outlines (top) indicate electrode positions and those in retinal outlines (bottom) indicate the location of receptive fields. In normal and trained animals (left and centre) the map is topographic (rows). In untrained animals (right), topography is lacking. Bold numbers represent robust responses, non-bold weak responses. Bottom panel: retinotectal topography as assessed anatomically. Dorsal view of the optic tectum after placements of the carbocyanine dyes DiI (square dotted lines) and DiAsp (round dotted lines) respectively in dorsal or ventral retina. A retinotopic map is observed in normal and trained, but not untrained (complete overlap of dye labelling), animals. Reproduced with permission from J. Neurotrauma.

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