Morphogens: What are they and why should we care?

Morphogens: What are they and why should we care?

Historic, Theoretical Mechanism of Action Nucleoprotein: the specific trophic cellular material extracted from the cell nucleus. DNA and RNA which regulates the structural regeneration of the cell Chromosome end-products made in the cell nucleus for normal functioning of the chromosomes Black Genetic Material Influencing cellular activity and response EcoRV homodimer in complex with a DNA substrate by Zephyris. CC BY-SA 3.0 2

Epigenetic Influence on Health Status Individual nutrient requirements influenced by genetic/environment and can play a role in nutrition therapy https://www.reading.ac.uk/nutrition/researchactivities/ntr-nutrigeneticsandnutrigenomics.aspx http://image.slidesharecdn.com/9qtd7ldsriynhq6pg7ho-signature-bafcd16d8c5e75571219b1cb15a8964597b3b0b47417309edd7c53216f944073-poli- 150312064305-conversion-gate01/95/nutrigenetics-possibilities-and-limitations-in-the-treatment-of-overweight-and-obesity-7-638.jpg?cb=1426151279 3

Multiple Factors Predict your Patients Health Trajectory Lifestyle, Environment, Diet Metabolic Control Epigenetic Expression Genetic Predisposition Methylation Transcriptomics Proteomics-Metabolomics mirna Neuro-Immune Controls & Responses Immune Modulation Endocrine Balance & Response ACTH MSH Inflammation Health Concerns Immuno - Resolution 4

Described Genetic Material Influences Metabolic Processes It is becoming increasingly evident that microparticles can exert functional effects on target cells indicating that these vesicles are more than just biomarkers of disease, and instead should be considered as circulating bioactive effectors of immunity. These microstructures are endogenously designed to incorporate selective components or morphogens from their donor cell, suggesting their generation is an active rather than passive budding process, and may also allow microparticles to target specific/distinct cell types/niches. J.Dalli and C. Serhan 2013 Norling, L. V. and J. Dalli (2013). "Microparticles are novel effectors of immunity." Current opinion in pharmacology 13(4): 570-575. Dalli, J., L. V. Norling, et al. (2014). "Microparticle alpha 2 macroglobulin enhances pro resolving responses and promotes survival in sepsis." EMBO Molecular Medicine 6(1): 27-42 5

Cellular Microparticles Demonstrated to Impact Epigenetic Influence Key Metabolic Influences of Major Metabolic Pathways: Not Only Methylation but also mirna as epigenetic effect mirna interactions with Inflammatory Pathways mirna important co-factor in Resolution of Inflammation Norling, L. V. and J. Dalli (2013). "Microparticles are novel effectors of immunity." Current opinion in pharmacology 13(4): 570-575 6

Defined cellular microparticles Having Key Roles in Chronic Health Management Morphogenic Cellular Particles including mrna and mirna work in conjunction with other cellular components to help modulate the immune cascade. Systematic Response Helps Resolve inflammation and minimize or control the cascade to chronic inflammatory response syndromes Norling, L. V. and J. Dalli (2013). "Microparticles are novel effectors of immunity." Current opinion in pharmacology 13(4): 570-575 7

Morphology Balanced cell signaling and metabolic processes Immune Modulation Immunogenic Response and Controls 8

Major Epigenetic Influencers of Health Expression Noncoding RNAs Health Outcome Histone Modifications DNA Methylation 9

Playing Foundational Roles in Nutrition Therapy and Adjunctive Patient Support 1. Supporting programs of care to resolve underlying inflammatory responses and normal cell and metabolic functions, 2. Adjunctive nutrition support for CNS response and functional neurology, 3. Support and stabilize healthy gut function to modulate immune responses, 4. Support healthy response of endocrine system support for Thymus, Adrenal, Thyroid functions 5. Support healthy response of cardiovascular systems 6. Provides underlying systems support and stabilization for routine chiropractic care 10

Axis of Influence Morphogenic Materials are Epigenetic Influencers CIRS Axis of Influence and Control Chronic Fatigue Digestive Function Metabolic Control 11

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Epigenetic Controls Micro-RNA (mirna) Non-protein coding sequence derived from DNA, evolutionarily conserved First discovered in 1993 ~18-22 nucleotides in length Regulate gene expression by binding to their complementary sites within the 3 untranslated regions (3 UTR) of target mrna Transcribed by RNA polymerase II in the nucleus to form large pri-mirna transcripts that are trimmed by the RNase III enzymes Leads to inhibition of translation or mrna degradation mirnas control the postranscriptional regulation of 30% of mammalian genes mirnas regulate gene expression and immune function Milenkovic, D., et al. mirna as molecular target of polyphenols underlying their biological effects. Free radical biology & medicine 2013; 64: 40-51. 13

Epigenetics: mirna binds the 3 UTR of mrna 60% of human protein-coding genes are regulated by mirna ~1,800 high confidence mirnas are encoded in the human genome (1.8% of the transcriptional output) Cui, J., B. Zhou, et al. (2017). "Nutrition, micrornas, and Human Health." Adv Nutr 8(1): 105-112. Cunningham-Rundles, S., D. F. McNeeley, et al. (2005). "Mechanisms of nutrient modulation of the immune response." Journal of Allergy and Clinical Immunology 115(6): 1119-1128. 14

The Most Significant Control Mechanism is the Modulation of the Inflammatory Response & Its Resolution 1. Epigenetic Controllers & Cell Signaling major systems of the metabolic processes; resolution of inflammation and control mechanisms of underlying conditions responses. This leads to its 2. Systems of Impact Inflammatory Pathways, Central Nervous System, Metabolic Systems, Digestive Health and more 15

A New Clinical Paradigm of Inflammation Two Key Phases Resolving the Process and Controlled by Macrophage Activation through Cell Signaling by mirna s Serhan CN. Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation. The American Journal of Pathology. 2010;177(4):1576 1591. doi:10.2353/ajpath.2010.100322. 16

17 Macrophage Activation with mirna Resolves the Inflammatory Response Observed in Chronic Health Conditions

Fatty Acid Conversions for Immuno-Resolution are Influenced by Morphogenic Materials and Leads to Epigenetic Expression and Response Immuno-Modulation and Immuno-Resolution Influence the Up and Down Regulation of LOX 5 and COX2 For Effective Control of the Resolution of Inflammation 18

Resolvins Interact with System Cell Receptors to Activate Morphogenic Material Leading to A pathway of Resolution of Inflammation mirna s shown to increase levels of IL-10 in macrophages Interaction of receptor activation and mirna morphogenic response 19

20 mirna s Have Been Mapped to Condition Specific Metabolic Pathways and Signals

Metabolic Axis of Care Inter-related Systems of Care Metabolic Function Gut/Liver Brain Endocrine Immune Control Modulation & Resolution Immune Nervous System HPA Axis Endocrine Control 21

Hierarchical Systems Controls: Transcriptomics and Proteomics Influence protein synthesis and receptor regulation Epigenetics influences system expression and function directly related to health outcome Key receptors and pathways identified and associated with various health issues mirna s 155, 181, 203, 218, 410, and a number of others shown to be associated with specific health needs 22

23 Multiple Roles of Microparticles and Morphogenic Material with mirnas support normal functional capacity and response of core systems

Cell Signaling and Epigenetic Influence Are Key Supportive Mechanisms: Neuro-Immune Modulation and Epigenetics Play are Controlling Mechanisms Effecting Functional Responses of the HPA Axis 24

25 Immune cells of the Central Nervous System (microglial cells) are activated and regulated by the CD33 Receptor activity influenced by mirna 181 and Resolvins. This results in an epigenetic influence and expression of CNS based compromised health status.

Seven Components of CNS Response Influenced by Immune Modulation and Epigenetics. Cell Signaling is Controlled and Balanced to Influence Normal Functional Capacity and Plasticity of the System Dysregulation is a result of altered epigenetic signaling influenced by lifestyles and nutrition Key receptors and signals are effected by mirna s 26

The Four Key Features & Capacities of the MiRNA in System Activity 1. Immune Modulation: Antigen Presentation & Oral Tolerance 2. Immune System Cascade & Response 3. Epigenetic Controllers & Cell Signaling major systems of the metabolic processes; resolution of inflammation and control mechanisms of underlying conditions responses 4. Systems of Impact Inflammatory Pathways, Central Nervous System, Metabolic Systems, Digestive Health and more 27

A sequence of events have been described to illustrate association of development of compromised health issues based on the systems biology and mechanisms of epigenetics. CD33 receptors in the CNS are responsible for functional activity of neurological activity mirna 181 regulates these receptors for normal cognitive function and neuronal functional activity New Diagnostic Tests are available to measure the status of these receptors 28