Activators of the cold stress response and uses thereof

The composition for use according to the preceding claims, wherein the Targeted Temperature Management therapy and/or the hypothermia therapy is a therapy wherein the internal core temperature of a subject is lowered between 3° and 36° C., such as between 3° and 35.5° C., between 3° and 35° C., between 3° and 34.5° C., between 3° and 34° C., between 3° and 33.5° C., between 3° and 33° C., between 3° and 32.5° C., between 3° and 32° C., between 3° and 31.5° C., between 3° and 31° C., between 3° and 30.5° C., between 30.5 and 36° C., between 30.5 and 35.5° C., between 30.5 and 35° C., between 30.5 and 34.5° C., between 30.5 and 34° C., between 30.5 and 33.5° C., between 30.5 and 33° C., between 30.5 and 32.5° C., between 30.5 and 32° C., between 30.5 and 31.5° C., between 30.5 and 31° C., between 31 and 36° C., between 31 and 35.5° C., between 31 and 35° C., between 31 and 34.5° C., between 31 and 34° C., between 31 and 33.5° C., between 31 and 33° C., between 31 and 32.5° C., between 31 and 32° C., between 31 and 31.5° C., between 31.5 and 36° C., between 31.5 and 35.5° C., between 31.5 and 35° C., between 31.5 and 34.5° C., between 31.5 and 34° C., between 31.5 and 33.5° C., between 31.5 and 33° C., between 31.5 and 32.5° C., between 31.5 and 32° C., between 32 and 36° C., between 32 and 35.5° C., between 32 and 35° C., between 32 and 34.5° C., between 32 and 34° C., between 32 and 33.5° C., between 32 and 33° C., between 32 and 32.5° C., between 32.5 and 36° C., between 32.5 and 35.5° C., between 32.5 and 35° C., between 32.5 and 34.5° C., between 32.5 and 34° C., between 32.5 and 33.5° C., between 32.5 and 33° C., between 33 and 36° C., between 33 and 35.5° C., between 33 and 35° C., between 33 and 34.5° C., between 33 and 34° C., between 33 and 33.5° C., between 33.5 and 36° C., between 33.5 and 35.5° C., between 33.5 and 35° C., between 33.5 and 34.5° C., between 33.5 and 34° C., between 34 and 36° C., between 34 and 35.5° C., between 34 and 35° C., between 34 and 34.5° C., between 34.5 and 36° C., between 34.5 and 35.5° C., between 34.5 and 35° C., between 35 and 36° C., between 35 and 35.5° C., or between 35.5 and 36° C.

An in vitro method for monitoring activation of the mild hypothermia response in a biological sample in response to a treatment, the method comprising the steps of:

• a) providing a first biological sample obtained from a mammal before administration of the treatment,
• b) contacting the first biological sample with an MHI construct comprising
• i. a promoter sequence of a gene selected from the group consisting of SP1, RBM3 and CIRBP;
• and
• i. a nucleic acid sequence encoding a detectable protein, wherein the detectable protein is selected from the group consisting of a fluorescent protein and a luminescent protein;
• c) determining the level of fluorescence or luminescence in the first biological sample,
• d) providing a second biological sample obtained from the same mammal after administration of the treatment,
• e) contacting the second biological sample with an MHI construct according to b,
• f) determining the level of fluorescence or luminescence in the second biological sample,
• wherein the mild hypothermia response is activated by the treatment if the fluorescence in the second biological sample is higher than in the first biological sample.

A method for monitoring activation of a mild hypothermia response in an individual following administration of a treatment, the method comprising the steps of:

• a) quantifying the amount of the protein encoded by one or more genes selected from the group consisting of:
• SMYD5, Mybl2, Hspg2, Xrn2, Fabp3, Ywhab, Phf20, Neo1, Tulp4, Trip12, Nt5e, Thrap3, Neat1, Rell1, Eif4g3, Ift52, Tfcp2l1, Fam21, Ctc1, Lamc1, Amotl2, Gabbr1, Hnrnpul1, Asxl1, Atp2b1, Atp2a3, Klf15, Cd24a, Tex15, Slc25a12, Slc35g1, Stag1, Pkn1, Vps41, Ewsr1, Acsf2, Ass1 in a first sample, wherein said first sample is obtained from the individual before said treatment;
• b) quantifying the amount of the protein encoded by one or more genes selected from the group consisting of:
• SMYD5, Mybl2, Hspg2, Xrn2, Fabp3, Ywhab, Phf20, Neo1, Tulp4, Trip12, Nt5e, Thrap3, Neat1, Rell1, Eif4g3, Ift52, Tfcp2l1, Fam21, Ctc1, Lamc1, Amotl2, Gabbr1, Hnrnpul1, Asxl1, Atp2b1, Atp2a3, Klf15, Cd24a, Tex15, Slc25a12, Slc35g1, Stag1, Pkn1, Vps41, Ewsr1, Acsf2, Ass1 in a second sample obtained from the same individual as in a), wherein said second sample is obtained after administration of said treatment;
• and
• c) comparing the amount of a protein quantified in a) and b);
• d) concluding that the mild hypothermia response is activated by the treatment if the amount of the protein quantified in b) is lower than in a),
• wherein a lower amount of protein encoded by one or more genes selected from the group consisting of:
• SMYD5, Mybl2, Hspg2, Xrn2, Fabp3, Ywhab, Phf20, Neo1, Tulp4, Trip12, Nt5e, Thrap3, Neat1, Rell1, Eif4g3, Ift52, Tfcp211, Fam21, Ctc1, Lamc1, Amotl2, Gabbr1, Hnrnpul1, Asxl1, Atp2b1, Atp2a3, Klf15, Cd24a, Tex15, Slc25a12, Slc35g1, Stag1, Pkn1, Vps41, Ewsr1, Acsf2, Ass1 in b) than in a) is indicative of that the treatment activates the mild hypothermia response.

An in vitro method for evaluating the effect of a candidate pharmacological agent for treatment of a disease or condition selected from the group consisting of:

• neonatal asphyxia, stroke, ischemia, cardiac arrest, migraine, traumatic brain injury, recovery after intense exercise, drug overdose, cerebral haemorrhage, subarachnoid haemorrhage (SAH), subdural hematoma (SH), cerebral infarction, cerebral vasospasm, spinal injury, neonatal abusive head trauma, brachial plexopathy, hair loss due to chemotherapy, chronic pain, neuropathic pain, and neurological pain, in an individual in need thereof, the method comprising the steps of:
• a) providing mammalian cells transfected with a MHI construct comprising
• i. a promoter sequence of a gene selected from the group consisting of SP1, RBM3 and CIRBP;
• and
• ii. a nucleic acid sequence encoding a detectable protein, wherein the detectable protein is selected from the group consisting of a fluorescent protein and a luminescent protein;
• b) measuring fluorescence or luminescence of the cells,
• c) contacting the cells with a candidate pharmacological agent,
• d) measuring fluorescence or luminescence of the cells after exposure to the candidate pharmacological agent,
• wherein a higher fluorescence or luminescence of the cells after exposure to the candidate pharmacological agent is indicative of the agent having an effect for treatment of said disease or condition.