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The Zinc Transporter ZNT2 (SLC30A2) as a Regulator of the Lactation Cycle: Implications in Suboptimal Lactation
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | The Zinc Transporter ZNT2 (SLC30A2) as a Regulator of the Lactation Cycle: Implications in Suboptimal Lactation. |
| 개인저자 | Rivera, Olivia C. |
| 단체저자명 | The Pennsylvania State University. Biomedical Sciences. |
| 발행사항 | [S.l.]: The Pennsylvania State University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 125 p. |
| 기본자료 저록 | Dissertations Abstracts International 80-12B. Dissertation Abstract International |
| ISBN | 9781392318867 |
| 학위논문주기 | Thesis (Ph.D.)--The Pennsylvania State University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Publisher info.: Dissertation/Thesis. Advisor: Soybel, David I. |
| 요약 | The benefits of breastmilk on infant and maternal health are well understood. Although breastfeeding initiation rates are high (~84% of infants in the United States), the percentage of women that exclusively breastfeed for the recommended 6 months period of time remains below 30%. Concern regarding poor milk production is among the top reasons for early infant weaning. Moreover, the prevalence of women who fail to lactate despite supportive intervention may be as high as 15%. Collectively, this suggests that biological factors play a greater role in poor lactation performance than currently recognized.To perform the highly coordinated and energetically demanding task of milk production and secretion, the mammary gland must undergo proper development and maturation. Following embyronic and postnatal development, the gland enters a cyclic pattern of development that repeats with each pregnancy. This cycle of lactation is characterized by expansion and proliferation of the gland during pregnancy, further morphological maturation and molecular coordination of milk production and secretion during lactation, and extensive cell death and tissue remodelling during involution, returning the gland to the pre-pregnancy state. Dysregulation of any stage along the lactation cycle can negatively impact milk production.The zinc transporter ZnT2 (SLC30A2) is critical for progression through the lactation cycle. ZnT2-mediated zinc transport is required for appropriate development of the mammary gland during puberty, establishment of polarity in mammary epithelial cells and expansion of the secretory system during lactation, and activation of programmed cell death in response to involution signals. Several polymorphisms in SLC30A2/ZnT2 have been identified in breastfeeding women, many of which compromise or augment ZnT2 function, suggesting that defects in ZnT2 function may play a role in poor lactation performance. Here we used genetic, physiologic, and epidemiologic approaches to assess the role of ZnT2 in lactation performance. We hypothesized that ZnT2-mediated regulation of lysosome function drives progression of the gland from a lactating to an involuting state. We further hypothesized that mutations in혻SLC30A2/ZnT2 alter lysosome function thereby impairing mammary epithelial cell function during lactation, resulting in suboptimal lactation.In study 1, we showed that ZnT2 is required for lysosome biogenesis and activity and is a key driver of mammary gland involution. Using ZnT2-null mice, we determined involution is delayed in the absence of ZnT2. Furthermore, we showed that ZnT2 interacts with the proton pump vesicular-ATPase (v-ATPase), and is required for assembly of v-ATPase on the lysosome membrane and acidification of the lysosome. This demonstrated that ZnT2 is required for the inititation of mammary epithelial cell death during involution, thereby regulating cessation of lactation.In study 2, we determined the impact of a mutation in SLC30A2/ZnT2 on milk volume. We found a common SLC30A2 mutation, substituting threonine for serine at amino acid residue 288 (S288), was found in women with low milk volume. Studies in vitro showed, S288 promoted ZnT2 phosphporylation and upregulated lysosome biogenesis and acidification. Furthermore, the mutation drives ZnT2 localization to the lysosome and lysosomal zinc accumulation, but interestingly, did not activate cell death. Instead, expression of S288 was associated with a reduction in cellular ATP. These findings suggest women harboring the S288 mutation may have defects in mammary epithelial cell energy metabolism, which may lead to reduced milk volume.Collectively, my dissertation addresses the influence of normal and dysregulated ZnT2 function on key mammary eptihelial cell properties that define breast function during the lactation cycle. Although numerous mutations and genetic variants in SLC30A2/ZnT2 have been identified in humans, our research provides the only direct evidence they cause mammary epithelial cell dysfunction in the context of lactation. Importantly, our findings demonstrate that genetic variation in SLC30A2/ZnT2 is a biological factor contributing to low milk supply, thereby providing a barrier to continued lactation success. Furthermore, my dissertation provides the first evidence of a genetic component that contributes to performance of the mammary gland during lactation in humans. Ultimately, these findings may aid in the development of screening methods or interventions to address lactation complications, thereby improving maternal and infant health. |
| 일반주제명 | Cellular biology. Nutrition. |
| 언어 | 영어 |
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