A5079287097- Cytokine Signaling Pathways and Interactions
- Estrogen and related hormone effects
- Hormonal Regulation and Hypertension
- Immune Response and Inflammation
- Endoplasmic Reticulum Stress and Disease
- Neonatal Health and Biochemistry
- Antifungal resistance and susceptibility
- Ion Transport and Channel Regulation
- interferon and immune responses
- Immunodeficiency and Autoimmune Disorders
- Systemic Lupus Erythematosus Research
- Pharmacological Effects of Natural Compounds
- T-cell and B-cell Immunology
- Ion channel regulation and function
- Diabetes and associated disorders
- RNA Research and Splicing
- Fungal Infections and Studies
- Inflammasome and immune disorders
- Immune Cell Function and Interaction
- NF-κB Signaling Pathways
- CRISPR and Genetic Engineering
- Erythrocyte Function and Pathophysiology
- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Phagocytosis and Immune Regulation
University of Pittsburgh
2016-2025
St. Jude Children's Research Hospital
2002-2024
Catalyst Biosciences (United States)
2024
Modus Therapeutics (Sweden)
2024
Washington University in St. Louis
2024
Acceleron Pharma (United States)
2024
Novartis (Switzerland)
2024
National Heart Lung and Blood Institute
2024
University of Maryland, College Park
2024
University of Iowa
2024
Abstract CD8 + T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as cell exhaustion, after persistent receptor stimulation in the tumor microenvironment (TME). Exhausted (T ex ) characterized by upregulation coinhibitory molecules and reduced polyfunctionality. TME experience an immunosuppressive metabolic environment via levels nutrients oxygen buildup lactic acid. Here we show that terminally uniquely upregulate Slc16a11 , which...
Abstract Caspase-1, also known as interleukin-1β (IL-1β)-converting enzyme (ICE), regulates antimicrobial host defense, tissue repair, tumorigenesis, metabolism and membrane biogenesis. On activation within an inflammasome complex, caspase-1 induces pyroptosis converts pro-IL-1β pro-IL-18 into their biologically active forms. “ICE −/− ” or “ Casp1 mice generated using 129 embryonic stem cells carry a 129-associated inactivating passenger mutation on the caspase-11 locus, essentially making...
Innate immune cells remember Immunological memory is a phenomenon by which can quickly recognize an antigen that the host has previously encountered. Certain of innate system exhibit memory-like responses know as trained immunity. Rapid, antigen-specific secondary (anamnestic) were long thought to be domain B and T cells. However, Dai et al. report monocytes macrophages acquire specific for particular major histocompatibility complex I antigens using paired A-type immunoglobulin-like...
The endosomal Toll-like receptor 7 (TLR7) is a major driver of murine and human systemic lupus erythematosus (SLE). role TLR7 in pathogenesis enhanced when the regulatory TLR9 absent. signaling plasmacytoid DCs (pDC) generally thought to be IFN response disease pathology; however, cell types which acts mediate have not been distinguished. To address this, we selectively deleted either CD11c+ cells or CD19+ cells; using TLR7-floxed allele, created on lupus-prone MRL/lpr background, along with...
Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STING
Suppressor of cytokine signaling 1 (SOCS1) is an obligate negative regulator and most importantly in vivo, via the interferon-gamma (IFN-gamma) receptor. SOCS1, its Src homology 2 domain, binds to phosphotyrosine residues targets, reducing amplitude from receptors. SOCS1 also implicated blocking Toll-like receptor (TLR) macrophages activated by TLR agonists such as lipopolysaccharide (LPS), thus regulating multiple steps activation innate immune responses. To rigorously test this, we...
The two highly related signal transducers and activators of transcription (Stats), Stat5a Stat5b, are major mediators prolactin signaling in both the mammary gland ovary. Deficiencies or result loss pregnancy during midgestation correlated with an increase ovarian 20α-hydroxysteroid dehydrogenase (20α-HSD) a decrease serum progesterone, which normally declines only immediately before parturition. To determine relative contribution 20α-HSD to progesterone metabolism Stat5 function...
Significance Psoriasis is a complex inflammatory disease with clear genetic contribution that affects roughly 2% of the population in Europe and North America. Inflammation skin, many cases joints, leads to severe clinical symptoms, including disfiguration disability. Immune cells their effector functions have been identified as critical factors for development; however, how susceptibility contributes remains largely unclear. Here we developed mouse models based on gene TNIP1 , whose...
Interleukin-4 (IL-4) induces tyrosine phosphorylation of the latent transcription factor Stat6, which mediates transcriptional responses IL-4. The trans-activation domain Stat6 has recently been mapped to C-terminal region Stat6. We have investigated mechanism by through its transactivation domain, transcription. Previous studies shown that diverse regulated factors interact with coactivators such as p300 and CBP. report used interaction p300/CBP exert stimulatory effects. Overexpression...
An allelic variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), PTPN22R620W, is strongly associated with 1 diabetes (T1D) in humans and increases the risk T1D by two- to fourfold. The NOD mouse a spontaneous model that shares many genetic pathways contributing T1D. We hypothesized introduction murine orthologous Ptpn22R619W mutation genome would enhance development microinjected CRISPR-Cas9 homology-directed repair template into single-cell zygotes introduce its endogenous...
Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and thought to play an important role pathogenesis hypertrophic cardiomyopathy (HCM), disease caused by sarcomere gene mutations. We hypothesized that microvascular HCM was secondary abnormal growth could occur independent ventricular hypertrophy.
Physiological adaptations to fasting enable humans survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization fatty acids glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical adaptive response. Here we discovered an alternative mechanism lipolysis adipocytes involving a lysosomal program....
CD28 ligation provides critical signals that modulate activated T cell fate. In a human to mouse reverse-engineering approach, single amino acid substitution adjacent the C-terminal proline-rich domain created A210P mice with enhanced signaling. experienced pro-inflammatory responses superagonist antibody, analogous severe cytokine storm induced in clinical trial, striking increase of CD8 cells. acute and chronic viral infections, early activation expansion effector cells increased,...
Abstract Sex steroids play a crucial role in the development and differentiation of normal mammary gland as well regulation breast cancer growth. Local intracrine formation sex from inactive precursors secreted by adrenals, namely, dehydroepiandrosterone its sulfate, may regulate growth function peripheral target tissues, including breast. Both endocrine paracrine influences on proliferation human cells are recognized. Breast tumors harbor tumor-associated macrophages tumor-infiltrating...
Molecular chaperones are responsible for maintaining cellular homeostasis, and one such chaperone, GRP170, is an endoplasmic reticulum (ER) resident that oversees both protein biogenesis quality control. We previously discovered GRP170 regulates the degradation assembly of epithelial sodium channel (ENaC), which reabsorbs in distal nephron thereby salt-water homeostasis blood pressure. To define role - and, more generally, molecular kidney physiology we developed inducible, nephron-specific...