Doctor of Philosophy, The Ohio State University, 2024, Molecular, Cellular and Developmental Biology

Heart failure (HF) is one of the leading causes of morbidity and mortality globally. A growing body of evidence has indicated the 5-year mortality rates are about ~50% after initial HF diagnosis. Electrolyte imbalances have been implicated in predicting the outcome of HF patients, where lower serum sodium levels (hyponatremia; serum sodium <135mEq) have been strongly associated with increased mortality in HF. Hence, serum sodium levels have been a well-established adverse prognostic marker for patients with chronic HF. Recent evidence has suggested that lower serum chloride (hypochloremia, <97mEq) is associated with increased mortality risk in patients with chronic HF independent of serum sodium levels. Even though hypochloremia is associated with increased mortality in HF patients, the exact role of chloride (Cl ) homeostasis in cardiac function and how hypochloremia contributes to cardiac injury is unknown. Hence, our study focuses on understanding the mechanism of hyperchloremia-mediated ischemia-reperfusion (IR) injury and the role of Cl- channel in mediating hypochloremia effects. In the first part of this dissertation, we showed that hypochloremia increases mortality in left ventricular assist device (LVAD) placement and acute decompensated HF (ADHF) patients. This increase in mortality was associated with aggravated myocardial infarction post IR injury from our ex vivo studies with isolated rat hearts. In cardiac physiology, hypochloremia increases the beating of hiPSC-CM, which is attributed to increased intracellular calcium (Ca2+) cycling. Since hypochloremia affects the Cl- homeostasis, the mitochondrial functions: membrane potential, and reactive oxygen species production are affected post IR injury. In the second part of this thesis, we have explored the involvement of Cl- channel downstream of hypochloremia on intracellular Ca2+ cycling. Two Cl- channel inhibitors, 4,4'-Diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt (DIDS), non-specific pl (open full item for complete abstract)

Committee: Harpreet Singh (Advisor); Sandor Gyorke (Committee Chair); Mahmood Khan (Committee Member); Nuo Sun (Committee Member) Subjects: Biochemistry; Biology; Biophysics; Cellular Biology; Molecular Biology

Bachelor of Science (BS), Ohio University, 2012, Biological Sciences

Cell migration is an essential biological process. In addition to being required for development and maintenance, cell motility also contributes to human disease. For example cancer metastasis is dependent on tumor cells gaining motility and traveling to secondary sites within the body. Cell motility requires the formation of protrusive structures including filopodia and lamellipodia. The formation of these structures requires rearrangement and coordinated organization of the actin cytoskeleton. Here I show that Drosophila Clic, a member of the CLIC family, contributes to the formation of filopodia by regulating the nucleation and elongation of these structures. This is done by examining the localization of Clic and genetic interactions with known cytoskeleton regulators. I show that there are three phases of filopodia formation,supported by the observed genetic interactions. I provide evidence that Clic is involved in all three phases of filopodia formation and interacts with Cell division cycle 42 (Cdc42), Diaphanous (Dia), Wiskott - Aldrich syndrome protein (WASp), the Actin related protein (Arp) 2/3 complex, Moesin (Moe), and Enabled (Ena). I also show that Clic may contribute to in vivo cell migration through the study of hemocyte migration in Drosophila embryos.

Committee: Dr. Soichi Tanda PhD (Advisor); Dr. Mark Berryman PhD (Advisor) Subjects: Cellular Biology; Genetics