Priority 1: Studying Molecular and Cellular Mechanisms of Health and Disease in Humans and Understanding the Resulting Phenotypes and Endotypes

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Molecular and cellular processes are fundamentally responsible for all biology. Research detailing basic biological functioning has led to effective approaches to health maintenance and to disease prevention, diagnosis, and treatment. However, additional comprehensive research into molecular and cellular mechanisms is needed to further develop the knowledge base necessary for more targeted interventions. Including sex as a biological variable is of heightened importance, as sex can influence molecular and cellular processes, clinical characteristics, and health and disease outcomes.

To continue making the most impactful advances, the fact that various biological mechanisms can give rise to a single disease presentation, or phenotype, must be considered. Being able to classify individual patients’ diseases by mechanism, or endotype, is also particularly valuable. Advances in biospecimen and data analysis tools over the past five years make such research possible. For example, molecular analyses with bulk, single cell, and single nucleus-based omics technologies can be used to identify unique and shared signaling pathways that provide mechanistic insights and therapeutic targets for diseases of interest to NIAMS.

Examples under this topic include the following.

Strategy 1.1: Elucidating Interactions Contributing to Arthritis or Musculoskeletal or Skin Diseases

• Exploring how cell-cell, tissue, and interorgan interactions contribute to healthy or diseased tissues of interest to NIAMS. This could include:
  • Understanding the role of immune cells and the immune system in bone, joint, muscle, and skin health and deterioration due to injury and disease (e.g., through the discovery of novel pathways that govern immune responses in these and other tissues of interest to NIAMS).
  • Studying tissue or organ crosstalk in the context of the health benefits of physical activity on conditions of interest to NIAMS.
  • Exploring the roles of adipose tissue in skin homeostasis and wound healing.
  • Defining the roles of the extracellular matrix’s interactions with cells in health and disease.
• Understanding the roles of various microbiomes (e.g., skin, gut) in the prevention, development, and treatment of diseases within the NIAMS mission.
• Studying the interactions between viral infections, vaccines, or antiviral treatments and NIAMS-relevant diseases. This could include:
  • Understanding the role of viral or host factors or interaction of these factors, or the role of antiretroviral therapy, in accelerating or worsening or early onset of diseases covered by NIAMS mission areas in people living with HIV.
  • Determining the influence of SARS-CoV-2 infection or COVID-19 vaccines or treatments, alone or in combination with host factors, on the health of people who have autoimmune diseases of interest to NIAMS.
• Defining the influences of endogenous biophysical factors in cell and tissue homeostasis and disease pathogenesis in the context of NIAMS mission areas. This could include:
  • Further characterizing how mechanical properties of the tissue microenvironment influence cell behavior.
  • Elucidating the impact of endogenous electric or magnetic fields on cell and tissue health.

Strategy 1.2: Understanding Mechanisms of Pain and Itch in Diseases of Interest to NIAMS

• Exploring the molecular and cellular origins of pain in people who have arthritis or who have musculoskeletal or skin diseases. This could include:
  • Studying those who experience joint pain in the absence of detectable musculoskeletal abnormalities, as well as those who have severe musculoskeletal defects but do not report pain.
  • Exploring the underpinning of sex differences in pain sensitivity and analgesic responses.
• Mapping innervation by neuronal subtypes in tissues related to diseases within the NIAMS mission.
• Defining the molecular and cellular underpinnings of neuro-inflammation and inflammation resolution related to pain in NIAMS mission areas.
• Studying the mechanisms underlying the relation between chronic pain and fatigue in diseases of interest to NIAMS.
• Translating findings related to the mechanisms of exercise-induced hypoalgesia (a decreased sensitivity to painful stimuli) into potential non-addictive pain relief approaches.

Strategy 1.3: Exploring Additional Mechanisms Contributing to Health and Disease

• Determining the mechanisms that underlie the effects of circadian rhythm disruptions on diseases within the NIAMS mission.
• Defining the mechanisms of action and disease progression for rare diseases or for understudied conditions to identify druggable targets.
• Understanding shared mechanisms (e.g., immunity and inflammation) in health and among diseases.
• Characterizing molecular and phenotypic heterogeneity within single diseases.
• Using modern approaches to discover, validate, and quantify biomarkers for use in disease diagnosis and prognosis and in evaluation of potential therapies.
• Exploring the molecular and biochemical factors responsible for sex differences in tissues involved in arthritis, musculoskeletal or skin conditions; disease susceptibility; and treatment response. This could include:
  • Studies of hormonal influences during adolescence or perimenopause or during hormone treatments.