<p>Atherosclerosis is a multi-factorial disease and is the major cause of death in the western world. Numerous risk factors, including hyperlipidemia, obesity, diabetes, smoking, hypertension, and family history increase the risk of atherosclerosis and death from cardiovascular disease (CVD). Clinical and epidemiological studies have now shown that hyperhomocysteinemia (HHcy) is an independent risk factor for CVD. Further, we and others have demonstrated that HHcy accelerates atherosclerosis in apolipoprotein Edeficient ( apoff1-) mice. Although several studies have reported that homocysteineinduced endoplasmic reticulum (ER) stress causes growth arrest and programmed cell death (PCD) in cultured vascular endothelial cells, the cellular factors responsible for this effect and their relevance to atherosclerosis have not been completely elucidated.</p><p>Previously, we have demonstrated that homocysteine induces the expression of Tcell death associated gene 51 (TDAG51), a member of the pleckstrin homology-related domain family, in cultured human vascular endothelial cells. Transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion and promoted detachment-mediated PCD. In support of these in vitro findings, TDAG51 expression was increased and correlated with PCD in the atherosclerotic lesions from apoff1-mice fed hyperhomocysteinemic diets, compared to mice fed control diet. To investigate the in vivo significance of TDAG51 on atherosclerotic lesion development and progression, knockout mice deficient in both TDAG51 and apoE genes were generated. Our findings show that TDAG51-1-/apoff1-double knockout (DKO) mice fed control chow diet have significantly reduced atherosclerotic lesion size, compared to ageand sex-matched apoff1-control mice. Atheroprotective function of TDAG51 deficiency may be explained in part by the observation that there is a significant upregulation of peroxisome proliferator-activated receptor y (PPAR-y) in TDAG51-deficient (TDAG51 _1_) cells including mouse embryonic fibroblasts (MEFs), compared to control wildtype MEFs. Given that PPAR-y has both atheroprotective and anti-inflammatory properties, TDAG51 may represent a unique negative regulator of PPAR-y and its downstream gene targets. Taken together, my findings demonstrate that TDAG51 is a novel cellular mediator involved in the development and progression of atherosclerosis.</p><p>In addition to its anti-atherogenic properties, I have demonstrated that TDAG5 l _1_ MEFs have increased migratory properties following monolayer disruption or in response to chemotaxis on fibronectin-coated Boyden chambers, compared to wildtype control MEFs. Although TDAG51-induced cell migration could potentially affect atherosclerotic lesion development, our recent observations suggest that TDAG51 may also have a role in wound healing. Our studies have shown that dorsal skin wounds within TDAG5 l _ 1_ mice healed slowly, compared to those in control mice through a mechanism involving impaired myofibroblast differentiation. Since the underlying mechanisms of wound healing and fibrosis are similar, it is conceivable that TDAG51 may have role in fibrosis.</p><p>In summary, this thesis provides novel evidence that TDAG5 l is involved in the pathogenesis of atherosclerosis and wound healing. Furthermore, TDAG51 may represent a novel therapeutic target for attenuating atherosclerotic lesion development, thereby reducing the risk of cardiovascular disease and its complications.</p> / Thesis / Doctor of Philosophy (PhD)

CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24+) cells and bystander (p24-) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24+ cells had longer telomeres compared to p24- cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24+ cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.