In the study of alphaA-crystallin (CRYAA), G98R CRYAA was cloned into a mammalian expression vector pcDNA6-His/myc version B and the sequence was confirmed by direct sequencing. Following lipophilic transfection to lens epithelial B3 cells, the recombinant mutated CRYAA protein was highly insoluble upon 0.5% Triton X-100 (Tx) extraction. It was retained and formed aggregation, and distributed in the endoplasmic reticulum (ER) along with the ER resident protein (protein disulfide isomerise). The wild-type (WT) CRYAA was found to be soluble and diffusely distributed in the cytoplasm. The accumulation of G98R mutant induced ER stress, and the affected cells were prone to apoptosis. After treatment with a small chemical molecule, the natural osmolyte trimethylamine N oxide (TMAO), the Tx insolubility of mutant protein was reduced in dose- and time-dependent manners. It was also prone to be degraded via ubiquitin proteasome pathway (UPP). In mutant-expressing cells, the mutant protein aggregation was decreased after treatment. The ER stress and the rate of apoptosis were also alleviated, probably mediated by heat shock response, as demonstrated by the effect of TMAO on heat shock protein 70 expression. / The third eye gene model was myocilin (MYOC ), the first identified gene responsible for primary open angle glaucoma. The aim of this study was to investigate if glaucoma-causing MYOC variants, including D384N MYOC, could be correctable. D384N MYOC was identified in a Chinese family diagnosed with high tension juvenile-onset primary open-angle glaucoma. Disease causing mutations in MYOC (R82C, C245Y, Q368X P370L, T377M, D380A, D384N, R422C, R422H, C433R, Y437H, I477N, I477S and N480K) were cloned into mammalian expression vector p3XFLAG-myc-CMV"-25 and the sequences confirmed by direct sequencing. Following lipophilic transfection to human trabecular meshwork (HTM) cells, the Tx solubility and secretion of MYOC and cell apoptosis were examined in the presence or not with small chemical treatments. 4-PBA, TMAO and deuterium oxide (D2O), reduced the portion of insoluble fractions to various extents in the mutant proteins. The osmolytes TMAO and D2O were more effective than 4-PBA in improving MYOC solubility. TMAO was further shown to improve the secretion and ER-Golgi trafficking of D384N MYOC, thereby reducing the ER stress and rescuing cells from apoptosis. (Abstract shortened by UMI.) / The truncated G165fsX8 gammaD-crystallin ( CRYGD) variant was studied to further examine the effects of small chemical-assisted protein rescue of a CRYGD mutant that causes congenital cataract. G165fsX8 CRYGD was identified in a Chinese family with nuclear type of congenital cataract. The mutation was cloned into a mammalian expression vector p3XFLAG-myc-CMV"-25 and sequence was confirmed by direct sequencing. Following lipophilic transfection to COS-7 cells, the G165fsX8 CRYGD mutant protein was significantly insoluble upon 0.5% Tx extraction and was mistrafficked to the nuclear envelope with co-localization with nuclear lamins, whereas WT protein was Tx soluble and nuclear located. Treatment with small chemical sodium 4-phenylbutyrate (4-PBA) substantially reduced the Tx insolubility and reversed the mutant protein to nuclear localization. This correction has resulted in better cell survival, probably via a heat-shock response, as demonstrated by heat-shock protein 70 up-regulation. / To date, many genes and mutations are identified to cause various ocular diseases. Some of them result in a disruption of protein folding, an important cause of disease pathogenesis and progression. In my laboratory, novel mutations of crystallins and myocilin have been identified to segregate with congenital cataract and primary open-angle glaucoma, respectively. In this thesis, I reported molecular investigations of the resultant protein variants and their altered cellular functions in relation to the clinical phenotypes that contributed to new understanding of the roles of these genes in ocular tissues. / Gong, Bo. / Adviser: Chi-Pui Pang. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 163-188). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.