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Oxytocin induces embryonic diapause
Minder, Jessica L; Winokur, Sarah B; Stephens, Janaye; Tong, Jie; Cassel, Naomi L; Schuster, Luisa; Issa, Habon A; Cammer, Michael; Khatri, Latika; Moisan, Gaia; Alvarado-Torres, Maria; Aristizábal, Orlando; Wadghiri, Youssef Z; Kim, Sang Yong; Valtcheva, Silvana; Lu, Catherine Pei-Ju; Chao, Moses V; Froemke, Robert C
Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.
PMCID:11881891
PMID: 40043121
ISSN: 2375-2548
CID: 5809752
Collagen-targeted Protein Nanomicelles for the Imaging of Non-Alcoholic Steatohepatitis
Wang, Andrew L; Mishkit, Orin; Mao, Heather; Arivazhagan, Lakshmi; Dong, Tony; Lee, Frances; Bhattacharya, Aparajita; Renfrew, P Douglas; Schmidt, Ann Marie; Wadghiri, Youssef Z; Fisher, Edward A; Montclare, Jin Kim
In vivo molecular imaging tools hold immense potential to drive transformative breakthroughs by enabling researchers to visualize cellular and molecular interactions in real-time and/or at high resolution. These advancements will facilitate a deeper understanding of fundamental biological processes and their dysregulation in disease states. Here, we develop and characterize a self-assembling protein nanomicelle called collagen type I binding - thermoresponsive assembled protein (Col1-TRAP) that binds tightly to type I collagen in vitro with nanomolar affinity. For ex vivo visualization, Col1-TRAP is labeled with a near-infrared fluorescent dye (NIR-Col1-TRAP). Both Col1-TRAP and NIR-Col1-TRAP display approximately a 3.8-fold greater binding to type I collagen compared to TRAP when measured by surface plasmon resonance (SPR). We present a proof-of-concept study using NIR-Col1-TRAP to detect fibrotic type I collagen deposition ex vivo in the livers of mice with non-alcoholic steatohepatitis (NASH). We show that NIR-Col1-TRAP demonstrates significantly decreased plasma recirculation time as well as increased liver accumulation in the NASH mice compared to mice without disease over 4 hours. As a result, NIR-Col1-TRAP shows potential as an imaging probe for NASH with in vivo targeting performance after injection in mice. STATEMENT OF SIGNIFICANCE: : Direct molecular imaging of fibrosis in NASH patients enables the diagnosis and monitoring of disease progression with greater specificity and resolution than do elastography-based methods or blood tests. In addition, protein-based imaging probes are more advantageous than alternatives due to their biodegradability and scalable biosynthesis. With the aid of computational modeling, we have designed a self-assembled protein micelle that binds to fibrillar and monomeric collagen in vitro. After the protein was labeled with near-infrared fluorescent dye, we injected the compound into mice fed on a NASH diet. Compared with that in control mice, the protein in these mice clears from the serum faster and accumulates significantly more in fibrotic livers. This work advances the development of targeted protein probes for in vivo fibrosis imaging.
PMID: 39236796
ISSN: 1878-7568
CID: 5688162
Mouse Cardiovascular Imaging
Phoon, Colin K L; Aristizábal, Orlando; Farhoud, Mohammed; Turnbull, Daniel H; Wadghiri, Youssef Z
The mouse is the mammalian model of choice for investigating cardiovascular biology, given our ability to manipulate it by genetic, pharmacologic, mechanical, and environmental means. Imaging is an important approach to phenotyping both function and structure of cardiac and vascular components. This review details commonly used imaging approaches, with a focus on echocardiography and magnetic resonance imaging, with brief overviews of other imaging modalities. In this update, we also emphasize the importance of rigor and reproducibility in imaging approaches, experimental design, and documentation. Finally, we briefly outline emerging imaging approaches but caution that reliability and validity data may be lacking. © 2024 Wiley Periodicals LLC.
PMCID:11371386
PMID: 39222027
ISSN: 2691-1299
CID: 5687622
Engineered coiled-coil HIF1α protein domain mimic
Britton, Dustin; Katsara, Olga; Mishkit, Orin; Wang, Andrew; Pandya, Neelam; Liu, Chengliang; Mao, Heather; Legocki, Jakub; Jia, Sihan; Xiao, Yingxin; Aristizabal, Orlando; Paul, Deven; Deng, Yan; Schneider, Robert; Wadghiri, Youssef Z; Montclare, Jin Kim
The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and in vivo tumor targeting capability.
PMID: 38656316
ISSN: 2047-4849
CID: 5663092
Coiled-Coil Protein Hydrogels Engineered with Minimized Fiber Diameters for Sustained Release of Doxorubicin in Triple-Negative Breast Cancer
Britton, Dustin; Legocki, Jakub; Paul, Deven; Katsara, Olga; Aristizabal, Orlando; Pandya, Neelam; Mishkit, Orin; Xiao, Yingxin; Aristizabal, Matias; Rahman, Neha; Schneider, Robert; Wadghiri, Youssef Z; Montclare, Jin Kim
Triple-negative breast cancer (TNBC) lacks expressed protein targets, making therapy development challenging. Hydrogels offer a promising new route in this regard by improving the chemotherapeutic efficacy through increased solubility and sustained release. Moreover, subcutaneous hydrogel administration reduces patient burden by requiring less therapy and shorter treatment times. We recently established the design principles for the supramolecular assembly of single-domain coiled-coils into hydrogels. Using a modified computational design algorithm, we designed Q8, a hydrogel with rapid assembly for faster therapeutic hydrogel preparation. Q8 encapsulates and releases doxorubicin (Dox), enabling localized sustained release via subcutaneous injection. Remarkably, a single subcutaneous injection of Dox-laden Q8 (Q8•Dox) significantly suppresses tumors within just 1 week. This work showcases the bottom-up engineering of a fully protein-based drug delivery vehicle for improved TBNC treatment via noninvasive localized therapy.
PMCID:11094684
PMID: 38622760
ISSN: 2373-9878
CID: 5655802
Protein-Engineered Fibers For Drug Encapsulation Traceable via 19F Magnetic Resonance
Britton, Dustin; Legocki, Jakub; Aristizabal, Orlando; Mishkit, Orin; Liu, Chengliang; Jia, Sihan; Renfrew, Paul Douglas; Bonneau, Richard; Wadghiri, Youssef Z; Montclare, Jin Kim
Theranostic materials research is experiencing rapid growth driven by the interest in integrating both therapeutic and diagnostic modalities. These materials offer the unique capability to not only provide treatment but also track the progression of a disease. However, to create an ideal theranostic biomaterial without compromising drug encapsulation, diagnostic imaging must be optimized for improved sensitivity and spatial localization. Herein, we create a protein-engineered fluorinated coiled-coil fiber, Q2TFL, capable of improved sensitivity to 19F magnetic resonance spectroscopy (MRS) detection. Leveraging residue-specific noncanonical amino acid incorporation of trifluoroleucine (TFL) into the coiled-coil, Q2, which self-assembles into nanofibers, we generate Q2TFL. We demonstrate that fluorination results in a greater increase in thermostability and 19F magnetic resonance detection compared to the nonfluorinated parent, Q2. Q2TFL also exhibits linear ratiometric 19F MRS thermoresponsiveness, allowing it to act as a temperature probe. Furthermore, we explore the ability of Q2TFL to encapsulate the anti-inflammatory small molecule, curcumin (CCM), and its impact on the coiled-coil structure. Q2TFL also provides hyposignal contrast in 1H MRI, echogenic signal with high-frequency ultrasound and sensitive detection by 19F MRS in vivo illustrating fluorination of coiled-coils for supramolecular assembly and their use with 1H MRI, 19F MRS and high frequency ultrasound as multimodal theranostic agents.
PMCID:10682962
PMID: 38037605
ISSN: 2574-0970
CID: 5591272
Towards reliable reconstruction of the mouse brain corticothalamic connectivity using diffusion MRI
Arefin, Tanzil Mahmud; Lee, Choong Heon; Liang, Zifei; Rallapalli, Harikrishna; Wadghiri, Youssef Z; Turnbull, Daniel H; Zhang, Jiangyang
Diffusion magnetic resonance imaging (dMRI) tractography has yielded intriguing insights into brain circuits and their relationship to behavior in response to gene mutations or neurological diseases across a number of species. Still, existing tractography approaches suffer from limited sensitivity and specificity, leading to uncertain interpretation of the reconstructed connections. Hence, in this study, we aimed to optimize the imaging and computational pipeline to achieve the best possible spatial overlaps between the tractography and tracer-based axonal projection maps within the mouse brain corticothalamic network. We developed a dMRI-based atlas of the mouse forebrain with structural labels imported from the Allen Mouse Brain Atlas (AMBA). Using the atlas and dMRI tractography, we first reconstructed detailed node-to-node mouse brain corticothalamic structural connectivity matrices using different imaging and tractography parameters. We then investigated the effects of each condition for accurate reconstruction of the corticothalamic projections by quantifying the similarities between the tractography and the tracer data from the Allen Mouse Brain Connectivity Atlas (AMBCA). Our results suggest that these parameters significantly affect tractography outcomes and our atlas can be used to investigate macroscopic structural connectivity in the mouse brain. Furthermore, tractography in mouse brain gray matter still face challenges and need improved imaging and tractography methods.
PMCID:10149621
PMID: 37060936
ISSN: 1095-9572
CID: 5464322
Evaluation of cellular water exchange in a mouse glioma model using dynamic contrast-enhanced MRI with two flip angles
Kiser, Karl; Zhang, Jin; Das, Ayesha Bharadwaj; Tranos, James A; Wadghiri, Youssef Zaim; Kim, Sungheon Gene
This manuscript aims to evaluate the robustness and significance of the water efflux rate constant (kio) parameter estimated using the two flip-angle Dynamic Contrast-Enhanced (DCE) MRI approach with a murine glioblastoma model at 7 T. The repeatability of contrast kinetic parameters and kio measurement was assessed by a test-retest experiment (n = 7). The association of kio with cellular metabolism was investigated through DCE-MRI and FDG-PET experiments (n = 7). Tumor response to a combination therapy of bevacizumab and fluorouracil (5FU) monitored by contrast kinetic parameters and kio (n = 10). Test-retest experiments demonstrated compartmental volume fractions (ve and vp) remained consistent between scans while the vascular functional measures (Fp and PS) and kio showed noticeable changes, most likely due to physiological changes of the tumor. The standardized uptake value (SUV) of tumors has a linear correlation with kio (R2 = 0.547), a positive correlation with Fp (R2 = 0.504), and weak correlations with ve (R2 = 0.150), vp (R2 = 0.077), PS (R2 = 0.117), Ktrans (R2 = 0.088) and whole tumor volume (R2 = 0.174). In the treatment study, the kio of the treated group was significantly lower than the control group one day after bevacizumab treatment and decreased significantly after 5FU treatment compared to the baseline. This study results support the feasibility of measuring kio using the two flip-angle DCE-MRI approach in cancer imaging.
PMCID:9945648
PMID: 36810898
ISSN: 2045-2322
CID: 5448162
Locus coeruleus activity improves cochlear implant performance
Glennon, Erin; Valtcheva, Silvana; Zhu, Angela; Wadghiri, Youssef Z; Svirsky, Mario A; Froemke, Robert C
Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.
PMID: 36544024
ISSN: 1476-4687
CID: 5395022
Open-source versatile 3D-print animal conditioning platform design for in-vivo preclinical brain imaging in awake mice and anesthetized mice and rats
Gironda, Zakia Ben Youss; Arefin, Tanzil Mahmud; Qayyum, Sawwal; Zhang, Jiangyang; Wadghiri, Youssef Zaim; Alon, Leeor; Yaghmazadeh, Omid
ORIGINAL:0016470
ISSN: 2692-8205
CID: 5417732