About

Professor Fred Sanford Gorelick is a distinguished researcher focused on the molecular mechanisms of acute pancreatitis. His laboratory investigates factors that sensitize the pancreas to disease development or influence its severity, with particular attention to the activation of digestive enzymes within the pancreatic acinar cell, where these enzymes are stored and contribute to acinar cell injury. Collaborative studies in his lab have identified renalase, a newly described survival factor, which significantly reduces injury in experimental models of acute pancreatitis by activating a plasma membrane calcium-export pump (PMCA4b) and other intracellular signaling pathways. Professor Gorelick's academic interests center on understanding the cellular and molecular processes underlying pancreatic injury and disease progression.

Research topics

• Medicine
• Biology
• Internal medicine
• Immunology
• Endocrinology
• Biochemistry
• Cancer research
• Pathology
• Psychotherapist
• Cell biology
• Environmental ethics
• Psychology
• Philosophy
• Physiology

Selected publications

• Renalase Activates Mitochondrial Leak Metabolism to Repair Mitochondrial Damage and Promote Cell Survival

  Journal of the American Society of Nephrology · 2025-10-01

  article
  PublisherDOI

• Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-06

  preprintOpen access

  High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

  PublisherOA PDFDOI

• Acute kidney injury markers in pediatric pancreatitis: Differentiating disease states and assessing severity

  Journal of Pediatric Gastroenterology and Nutrition · 2025-12-12

  articleOpen access

  OBJECTIVES: Acute kidney injury (AKI) is a complication commonly observed in adults with acute pancreatitis (AP) but remains poorly studied in pediatric patients. We investigated the utility of AKI biomarkers-kidney injury molecule-1 (KIM-1), lipocalin 2 (NGAL), cystatin-C (CYS-C), and renalase (RNLS) in acute and chronic pancreatitis (CP), and to assess AP severity, and evaluate kidney function. METHODS: Plasma and urine samples were collected from children with AP (n = 49), CP (n = 50), and healthy controls (HC; n = 20). AKI biomarkers levels were measured using enzyme-linked immunosorbent assays (ELISA). AP patients were categorized into two groups: mild AP (MAP) and moderate/severe AP (SAP). Kidney function was evaluated using plasma creatinine (pCre) and CYS-C-based enhanced glomerular filtration rate (eGFR) formulas. RESULTS: Plasma KIM-1 and pCYS-C were elevated in AP versus CP and HCs (p < 0.0001). Urinary NGAL (uNGAL) was elevated in AP subjects, with 14% of patients exceeding the value of 125 ng/mL. Plasma A-RNLS remained same between AP and HCs (p = 0.78) but was elevated in CP cohort (p < 0.0001). However, pF-RNLS levels declined in AP compared to HCs and CP (p < 0.0001). SAP subjects (20% of AP cohort) had elevated pKIM-1 and pCYS-C compared to MAP (p = 0.002, p = 0.003). eGFR declined in AP subjects with 84% of AP patients showing CYS-C eGFR <90 mL/min/1.73 m². Plasma CYS-C, pA-RNLS, and pF-RNLS predicted AP from CP with area under the receiving operating curve of 0.86 (95% CL). CONCLUSION: Elevated pKIM-1, pCYS-C, and uNGAL, along with declining pF-RNLS, are helpful in distinguishing pediatric AP from CP. Quantifying the Levels of pKIM-1 and pCYS-C within the first 48 h can help predict development of SAP.

  PublisherOA PDFDOI

• Renalase activates mitochondrial leak metabolism in response to cellular stress and to repair damage after injury

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-20 · 1 citations

  preprintOpen access

  A variety of mechanisms enhance cell stress response and repair; however, the role of mitochondria in this activity is unclear. Here we show that exogenous renalase (RNLS), an intracellular flavin-dependent NADH oxidase, activates intramitochondrial RNLS activity to promote cell survival. RNLS interacts with the ATP synthase alpha and beta subunits (ATP5α and ATP5β) and opens the ATP synthase c-subunit leak channel to increase complex I and II activities and protein synthesis rate. RNLS causes a selective, sustained, time-dependent increase in cellular protein synthesis without affecting cell proliferation, whereas RNLS deletion or direct inhibition of the mitochondrial leak blocks RNLS-mediated protein synthesis. Functional analysis of newly and differentially synthesized proteins over 24 hours reveals rapid changes in one-carbon metabolism and ribosomal biogenesis pathways as early as one hour after RNLS exposure. Mitochondrial injury is more severe in the RNLS KO kidney after acute stress, related to decreased protein synthesis rate and increased mitophagy. RNLS KO mice exposed to the stress of chronic cardiac pressure overload fail to develop cardiac hypertrophy, the physiological response, and die of heart failure and cardiac rupture. These data highlight the critical role RNLS has in activating mitochondrial leak metabolism to induce selective protein synthesis and protect against acute and chronic stress. HIGHLIGHTS: Renalase interacts with the ATP synthase alpha and beta subunitsRenalase activates mitochondrial leak metabolismRenalase and leak metabolism increase complex I and II activitiesLeak metabolism increases protein synthesis rateRenalase protects against cell stress and organ injury.

  PublisherOA PDFDOI

• A Metabolic Shift Caused by Renalase Interaction With Mitochondrial ATP Synthase

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Quest for an accurate and reproducible prognostic biomarker of severe acute pancreatitis: have we finally found it?

  HepatoBiliary Surgery and Nutrition · 2025-07-30

  letterOpen access
  PublisherDOI

• International Association of Pancreatology Revised Guidelines on Acute Pancreatitis 2025: Supported and Endorsed by the American Pancreatic Association, European Pancreatic Club, Indian Pancreas Club, and Japan Pancreas Society

  Pancreatology · 2025-07-15 · 52 citations

  articleOpen access
  PublisherOA PDFDOI

• Visceral pain-related acute actions of cerulein on mouse and human sensory neurons

  Molecular Pain · 2025-06-16 · 4 citations

  articleOpen access

  Cerulein is an orthologue of cholecystokinin, which is often used to induce acute pancreatitis in pre-clinical studies. In these models, animals show signs of pain, and this is the most common complaint of patients with acute pancreatitis. However, little is known about how this pain is mediated, the role of cerulein murine pain responses, or its relevance to human pancreatitis pain. We injected 25 or 50 µg/kg cerulein intraperitoneally into male and female mice and assessed pain behaviors using the von Frey test of mechanical hypersensitivity. The excitability of mouse and human visceral dorsal root ganglia (DRG) neurons was assessed using whole-cell patch-clamp electrophysiology. Pharmacology was performed using commercial antagonists of cholecystokinin (CCK) A or B receptors. We show that pain behaviors developed similarly in male and female cerulein-injected mice and that visceral DRG from these mice exhibited increased excitability compared to controls. Direct application of cerulein to T8-L2 mouse and human DRG showed increased excitability compared to controls consistent with DRG from cerulein-injected mice. The actions of cerulein on visceral DRG neurons were attributed to CCK-A, but not CCK-B receptor. A similar response to cerulein was observed in human thoracic DRG neurons. These findings highlight the importance of the cholecystokinin system, particularly the CCK-A receptor, to visceral pain including pancreatitis through direct sensitization of visceral DRG neurons from mice or humans.

  PublisherDOI

• Has a Hundred Years of Pursuing Proteases Helped to Palliate Pain in Chronic Pancreatitis More Than Placebo?

  Gastroenterology · 2024-02-02

  editorialOpen accessSenior author
  PublisherOA PDFDOI

• Interventions to support fellowship application success among predoctoral physician-scientists

  JCI Insight · 2024-03-08 · 7 citations

  reviewOpen access

  A critical element of physician-scientist training is the development and practice of core competencies that promote success in research careers. The ability to develop compelling training and research proposals is one such foundational skill. The NIH Ruth L. Kirschstein National Research Service Award (NRSA) individual fellowship for dual-degree students (F30, F31, or F31-Diversity) creates an ideal opportunity to provide formal instruction in grant-writing skills to physician-scientists early in training. In the guided process of preparing a predoctoral fellowship application, students learn to formulate clear short- and long-term research and training goals; construct a comprehensive, well-reasoned, and rigorous proposal; become familiar with funding agency priorities; and gain strategic insights into the peer review system. Beyond building scientific writing skills, the application process for an NRSA F30 or F31 is an opportunity for trainees to strengthen mentor-mentee relationships, identify learning opportunities key to their scientific development, and build effective research and mentoring teams. These skills also apply to developing future postdoctoral mentored K applications or faculty research program grants. Here, we outline key features of the structured proposal development training developed for students in the Yale MD-PhD Program and review outcomes associated with its implementation.

  PublisherOA PDFDOI

Recent grants

• Animal and Pathology Core

  NIH · $16.3M · 2021

• Exocrine pancreatic zymogen activation

  NIH · $3.9M · 1998–2020

• NIH Grant R01DK031506

  NIH · $144k · 1986

• NIH Grant I01BX000929

  NIH · 2015

• Training Program in Investigative Gastroenterology

  NIH · $7.9M · 1977–2027

Frequent coauthors

• Stephen J. Pandol

  Cedars-Sinai Medical Center

  83 shared

• Edwin C. Thrower

  VA Connecticut Healthcare System

  70 shared

• Thomas R. Kolodecik

  Yale University

  68 shared

• Gary V. Désir

  Yale University

  50 shared

• Paul Greengard

  Rockefeller University

  47 shared

• Taiichi Otani

  Tokyo Metropolitan Tama Medical Center

  39 shared

• Christine Shugrue

  Yale University

  38 shared

• Anna S. Gukovskaya

  VA Greater Los Angeles Healthcare System

  37 shared

Education

• M.D., Internal Medicine

  University of Missouri

• M.D., Gastroenterology

  Yale