By the end of the course, the student will be able to:

• Understand the molecular mechanisms of the Unfolded Protein Response (UPR), with particular focus on the three main signaling pathways (IRE1, PERK, and ATF6) and their role in maintaining endoplasmic reticulum homeostasis.

• Critically analyze the main pharmacological approaches for modulating the UPR, distinguishing between inhibitors and activators specific to the different branches of the pathway.

• Evaluate the therapeutic potential of pharmacologically targeting the UPR in relevant diseases such as neurodegenerative disorders, cancer, and metabolic diseases.

• Interpret experimental data from preclinical and clinical studies on UPR-targeting compounds, with particular attention to side effects and the specificity of pharmacological interventions.

I. Introduction to the UPR and Biological Context

• Function of the endoplasmic reticulum (ER) and causes of ER stress

• Activation and roles of the three UPR signaling pathways:

  • IRE1 (inositol-requiring enzyme 1)

  • PERK (PKR-like ER kinase)

  • ATF6 (activating transcription factor 6)

• Role of the UPR in cellular homeostasis and cell fate decisions

II. Pharmacological Targets within the UPR

• Rationale for pharmacological modulation of the UPR

• "Pro-survival" vs. "Pro-apoptotic" strategies

• Examples of pharmacological targets:

  • PERK inhibitors/activators (e.g., GSK2606414, ISRIB)

  • RNase inhibitors of IRE1α (e.g., MKC-3946)

  • ATF6 modulators (e.g., Ceapin-A7)

III. Preclinical Studies and Therapeutic Applications

• UPR and cancer: how certain tumor cells exploit the UPR for survival

• Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s)

• Metabolic diseases (e.g., diabetes, hepatic steatosis)

• Overview of compounds in preclinical and clinical development

IV. Case Study and Scientific Article Analysis

• Examples: one study on ERO1A in cancer and application of its inhibitors, another on ERO1 in muscular diseases and application of chemical chaperone such as TUDCA

• Analysis of experimental strategies, results, and therapeutic implications

V. Discussion and Conclusions

• Future perspectives and current challenges in pharmacological modulation of the UPR

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Knowledge and Understanding

The PhD student will acquire an advanced and critical understanding of the molecular mechanisms of the UPR and of the main pharmacological approaches developed to modulate it, including their relevance to complex diseases.

Applying Knowledge and Understanding

The student will be able to apply this knowledge to the analysis of scientific experiments, the design of research hypotheses, and the evaluation of the effectiveness of pharmacological compounds in cellular or animal models.

Making Judgements

The student will develop critical skills in evaluating scientific literature and preclinical/clinical data related to UPR modulation, also in the context of identifying new therapeutic targets.

Communication Skills

The student will be able to clearly and rigorously discuss UPR-related pharmacological strategies with the scientific community, using appropriate terminology and up-to-date literature.

Learning Skills

The course will stimulate the ability to independently learn about new developments in the field of cellular and molecular pharmacology, enabling the student to stay continuously informed about emerging technologies and innovative therapeutic approaches.

The teaching material prepared by the lecturer in addition to recommended textbooks (such as for instance slides, lecture notes, exercises, bibliography) and communications from the lecturer specific to the course can be found inside the Moodle platform › blended.uniurb.it

NA

Teaching

The course will be structured using an active and participatory teaching approach, designed to promote critical learning and the integration of theory with research. The planned methods include:

• Interactive lecture (with multimedia support):
  Presentation of fundamental concepts, the molecular pathways involved in the UPR, and the main pharmacological approaches. Throughout the lecture, questions and brief discussion moments will be encouraged to foster active reflection.

Attendance

NA

Course books

NA

Assessment

NA

Disability and Specific Learning Disorders (SLD)

Students who have registered their disability certification or SLD certification with the Inclusion and Right to Study Office can request to use conceptual maps (for keywords) during exams.

To this end, it is necessary to send the maps, two weeks before the exam date, to the course instructor, who will verify their compliance with the university guidelines and may request modifications.

Teaching

The course will be structured using an active and participatory teaching approach, designed to promote critical learning and the integration of theory with research. The planned methods include:

• Interactive lecture (with multimedia support):
  Presentation of fundamental concepts, the molecular pathways involved in the UPR, and the main pharmacological approaches. Throughout the lecture, questions and brief discussion moments will be encouraged to foster active reflection.

Attendance

NA

Course books

NA

Assessment

NA

Disability and Specific Learning Disorders (SLD)

Students who have registered their disability certification or SLD certification with the Inclusion and Right to Study Office can request to use conceptual maps (for keywords) during exams.

To this end, it is necessary to send the maps, two weeks before the exam date, to the course instructor, who will verify their compliance with the university guidelines and may request modifications.