Research Projects

Senescence is a physiological process that occur during placental development, and it thought to play important role in the initiation of parturition. Dysregulation of placental senescence can severely impact pregnancy outcomes and health of both the fetus and the mother. However, the mechanism that regulates placental senescence remains largely unknown and understanding this process is essential for elucidating the molecular basis of pregnancy complications such as pre-eclampsia and preterm birth. Our long-term goal is to understand role of genome maintenance and related pathways particularly cellular senescence in placental development and pregnancy outcomes. These discoveries will provide foundational knowledge of placental biology and may help in developing novel therapeutic strategies for pregnancy complications. The overall objective of this grant is to identify genes that regulates placental senescence and understanding their impact on pregnancy complications such as preeclampsia and preterm birth. The central hypothesis is that placental cells accumulate DNA damage in repetitive DNA sequences as gestation progresses and that this damage induces senescence. We further hypothesize that altered rates of DNA damage during pregnancy affects the timing and extent of placental senescence. The rationale for this study is that understanding mechanism of genome maintenance and its impact on placental senescence will help in understanding pregnancy related abnormalities. To test this hypothesis our specific aims are: 1. To perform a genome wide screening of genes regulating senescence in different human placental cell types. 2. To analyze genomic instability in repetitive DNA sequences, particularly transposable elements, and access their contribution to placental senescence. 3. To examine circulating markers of senescence in the maternal blood from pregnancies complicated by pre-eclampsia and preterm birth. For aim1 we have developed a CRISPRi screen using human trophoblast stem cells and differentiated cells. This will help to identify genes regulating senescence in placental cells in a genome wide manner. In aim 2 we will analyze effect of genomic instability at repetitive sequences with focus on transposons and their role in placental senescence and pregnancy complications. In aim 3 we will analyze senescence related genes expression and its role in pre-eclampsia and preterm birth placenta. This contribution is significant since it will provide critical knowledge gap in the field of reproductive biology with implications for maternal and fetal health. The proposed research is innovative because we are using cutting-edge genomics approaches, including CRISPRi screening and transposon instability analysis to investigate regulation of senescence in placental cells and its impact in pregnancy complication. Together these studies have potential to make substantial contribution to uncover novel mechanisms underlying pregnancy complications, paving the way of therapeutic strategies.