Two distinct NF[kappa]B signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune system development. The former is dependent on the I[kappa]B kinase adaptor molecule NEMO, and the latter is independent of it. My dissertation encompasses approaches including biochemistry, molecular biology, mouse genetics and computational simulations to investigate potential crosstalk mechanisms between these two pathways. Specifically, I describe evidence for two distinct mechanisms by which the non-canonical NF[kappa]B pathway determines the responsiveness of canonical pathway to inflammatory signals. In the first mechanism, low homeostatic non-canonical signaling in tissue fibroblasts allows for accumulation of the non-canonical I[kappa]B, I[kappa]B[delta], during pathogen inflammatory exposure. Accumulation of I[kappa]B[delta] thereby 242}0reduces RelA:p50 activity at late time points. In the second mechanism, elevated homeostatic non-canonical signaling in inflammatory dendritic cells results in the formation of a previously overlooked dimer, RelB:p50. RelB:p50 forms a complex with canonical I[kappa]B's and contributes to canonical signaling when cells are exposed to inflammatory stimuli. These observations suggest that NEMO-dependent and independent signaling should be viewed within the context of a single NF[kappa]B signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. Further, homeostatic regulation determines the responsiveness of the signaling system and perturbed homeostatic control renders pathological outcomes. As in other regulatory biological systems, a systems approach, including mathematical models that include quantitative and kinetic information, is useful to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.