Spheron components useful in determining compounds capable of treating symptoms of Alzheimer's disease, and treatments and animal models produced therefrom

• US 20040002460A1
• Filed: 03/04/2003
• Published: 01/01/2004
• Est. Priority Date: 03/04/2002
• Status: Abandoned Application

• Current Assignee: Nymox Corporation
• Original Assignee: Nymox Corporation
• Inventors: Averback, Paul
• Application Number:
  US10/378,065
• Publication Number:
  US 20040002460A1
• Time in Patent Office: Days
• US Class Current: 514/13
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein

Abstract

The present invention relates to protein components of spherons that are useful for identifying compounds capable of preventing and/or ameliorating symptoms of Alzheimer'"'"'s Disease and/or dementia associated with cerebral amyloidosis. The invention also relates to the compounds identified by the methods, and methods of treating and/or ameliorating symptoms of Alzheimer'"'"'s Disease and/or dementia associated with cerebral amyloidosis. The invention also relates to methods of making an Alzheimer'"'"'s Disease or dementia associated with cerebral amyloidosis animal model or test animal, the animal model produced therefrom, and to a method of using the animal model to screen for effective therapies.

Claims

1. A composition comprising:

at least one comopund that binds to, antagonizes, or competes with a spheron component peptide other than a spheron component responsible for forming amyloid plaque, the spheron component peptide being selected from one or more of the group consisting of;

a) GEAAGAVQELAR (SEQ ID NO.

     1);

b) GLSAASPPLAETGAPR (SEQ ID NO.

     2);

c) ARAEAQEAEDQQAR (SEQ ID NO.

     3);

d) VLAQLLR (SEQ ID NO.

     4);

e) ALAHLLEAERQER (SEQ ID NO.

     5);

f) AADHDVGSELPPEGVLGALLR (SEQ ID NO.

     6);

g) LETPAPQVPAR (SEQ ID NO.

     7);

h) ILAGSADSEGVAAPR (SEQ ID NO.

     8);

i) ARPVKEPRGLSAASPPLAETGAPRRF (SEQ ID NO.

     9);

j) ARPVKEP (SEQ ID NO.

     10);

k) GLSAASPPLAETGAPRRF (SEQ ID NO.

     11);

l) AADHDVGSELPPEGVLGALLRVKRLETPAPQVPA (SEQ ID NO.

     12);

m) AADHDVGSELPPEGVLGALLRV (SEQ ID NO.

     13);

n) LETPAPQVPA (SEQ ID NO.

     14);

o) RRSVPRGEAAG (SEQ ID NO.

     15);

p) VLAQLLRVWGAPRNSD (SEQ ID NO.

     16);

q) PALGLDDDPDAPAAQLAR (SEQ ID NO.

     17);

r) LARALLRARLDPAALAA (SEQ ID NO.

     18);

s) QLVPAPVPAAALRPRPPVYDD (SEQ ID NO.

     19);

t) GPAGPDAEEAGDE (SEQ ID NO.

     20);

u) TPDVDPELLRYLLGR (SEQ ID NO.

     21);

v) LLRVKR (SEQ ID NO.

     22); and

w) VLGALLRVKRLE (SEQ ID NO.

     23).

2. The composition as claimed in claim 1, further comprising a pharmaceutically acceptable buffer, diluent, adjuvant, carrier or combination thereof.

3. The composition as claimed in claim 1,-wherein the composition is capable of traversing the blood-brain barrier when administered to a patient.

4. The composition as claimed in claim 1, wherein the spheron component peptide is SEQ ID NO. 1.

5. The composition as claimed in claim 1, wherein the spheron component peptide is SEQ ID NO. 2.

6. The composition as claimed in claim 1, wherein the spheron component peptide is SEQ ID NO. 3.

7. The composition as claimed in claim 1, wherein the spheron component is SEQ ID NO. 4.

8. The composition as claimed in claim 1, wherein the spheron component peptide is SEQ ID NO. 5.

9. The composition as claimed in claim 1, wherein the spheron component peptide is SEQ ID NO. 6.

10. The composition as claimed in claim 1, wherein the spheron component peptide is SEQ ID NO. 7.

11. The composition as claimed in claim 1, wherein the spheron component is SEQ ID NO. 8.

42. The composition as claimed in claim 1, wherein the compound is an antibody, antibody fragment or short chain antibody with an affinity for proSAAS or a peptide fragment, domain or subunit thereof.

43. The composition as claimed in claim 1, wherein the compound is a peptide fragment, domain or subunit of proprotein convertase 1 (PC1) with an affinity for proSAAS or a peptide fragment, domain or subunit thereof.

44. The composition as claimed in claim 43, wherein the proprotein convertase is selected from the group of proprotein convertases comprising PC1 [also called PC3], PC2, PC4, PC6 [also called PC5], PACE4, LPC [also called PC7 or PC8] and furin.

49. The composition as claimed in claim 1, wherein the compound is a peptide fragment, domain or subunit of proprotein convertase 1 (PC1) with an affinity for proSAAS or a peptide fragment, domain or subunit thereof, the compound being an active site selected from the group consisting of:

ENKHG (SEQ ID NO.

     24);

LDGIVTDAIE (SEQ ID NO.

     25);

SWGPNDD (SEQ ID NO.

     26);

WASGNG (SEQ ID NO.

     27);

CDGYTDSIYTI (SEQ ID NO.

     28); and

HTGTS (SEQ ID NO.

     29).

12. A composition for treating dementia or cognitive impairment, comprising a pharmaceutically effective amount of a compound that functions in a manner selected from the group consisting of:

a) impedes or prevents the release from a spheron of proSAAS or a peptide fragment, variant, derivative, homologue, or mimetic thereof;

b) binds to, inhibits, antagonizes or competes with proSAAS or a peptide fragment, variant, derivative, homologue, or mimetic thereof that is released from a spheron;

c) reduces or prevents the cytotoxic effects of proSAAS or a peptide fragment, variant, derivative, homologue, or mimetic thereof that is released from a spheron; and

d) counteracts the effects of the release from a spheron component of proSAAS or peptide fragment, variant, derivative, homologue, or mimetic thereof.

13. The composition of claim 12, wherein the peptide fragment of proSAAS is one or more peptides selected from the group consisting of:

a) GEAAGAVQELAR (SEQ ID NO.

     1);

b) GLSAASPPLAETGAPR (SEQ ID NO.

     2);

c) ARAEAQEAEDQQAR (SEQ ID NO.

     3);

d) VLAQLLR (SEQ ID NO.

     4);

e) ALAHLLEAERQER (SEQ ID NO.

     5);

f) AADHDVGSELPPEGVLGALLR (SEQ ID NO.

     6);

g) LETPAPQVPAR (SEQ ID NO.

     7);

h) ILAGSADSEGVAAPR (SEQ ID NO.

     8);

i) ARPVKEPRGLSAASPPLAETGAPRRF (SEQ ID NO.

     9);

j) ARPVKEP (SEQ ID NO.

     10);

k) GLSAASPPLAETGAPRRF (SEQ ID NO.

     11);

l) AADHDVGSELPPEGVLGALLRVKRLETPAPQVPA (SEQ ID NO.

     12);

m) AADHDVGSELPPEGVLGALLRV (SEQ ID NO.

     13);

n) LETPAPQVPA (SEQ ID NO.

     14);

o) RRSVPRGEAAG (SEQ ID NO.

     15);

p) VLAQLLRVWGAPRNSD (SEQ ID NO.

     16);

q) PALGLDDDPDAPAAQLAR (SEQ ID NO.

     17);

r) LARALLRARLDPAALAA (SEQ ID NO.

     18);

s) QLVPAPVPAAALRPRPPVYDD (SEQ ID NO.

     19);

t) GPAGPDAEEAGDE (SEQ ID NO.

     20);

u) TPDVDPELLRYLLGR (SEQ ID NO.

     21);

v) LLRVKR (SEQ ID NO.

     22); and

w) VLGALLRVKRLE (SEQ ID NO.

     23).

14. The composition as claimed in claim 13, further comprising a pharmaceutically acceptable buffer, diluent, adjuvant, carrier or combination thereof.

15. The composition as claimed in claim 13, wherein the composition is capable of traversing the blood-brain barrier when administered to a patient.

16. The composition as claimed in claim 12, wherein the compound counteracts effects of the release by a spheron component of proSAAS or peptide fragment, variant, derivative, homologue, or mimetic thereof by counteracting the effects of one or more selected from the group consisting of:

a) abnormally inhibited activity of one or more proprotein convertase in the brain or in other neuroendocrine tissues caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

b) abnormally decreased adrenocorticotrophic hormone (ACTH) caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

c) abnormally decreased insulin caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

d) abnormally decreased enkephalins caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

e) abnormally decreased thyrotropin-releasing hormone (TRH) caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof; and

f) abnormally decreased dynorphin caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof.

17. The composition as claimed in claim 16, wherein the compound reduces or counteracts the inhibition of a proprotein convertase selected from the group consisting of PC1-PC8, and furin.

18. The composition as claimed in claim 12, wherein the compound counteracts the effects by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof, by increasing or otherwise altering at least one component selected from the group consisting of cerebral ACTH, cerebral insulin, cerebral enkephalins, cerebral TRH, cerebral dynorphin, cerebral α

MSH and β

endorphin, cerebral pro-insulin, cerebral pro-glucagon, cerebral glucagon-like peptide (GLP), cerebral pro-somatostatin, cerebral pro-pancreatic peptide, cerebral pro-GHRH, cerebral neuropeptide melamin-concentrating hormone, cerebral NEI, cerebral neurotensin, and cerebral opioid peptides.

45. The composition as claimed in claim 12, wherein the compound is an antibody, antibody fragment or short chain antibody with an affinity for proSAAS or a peptide fragment, domain or subunit thereof.

46. The composition as claimed in claim 12, wherein the compound is a peptide fragment, domain or subunit of proprotein convertase 1 (PC1) with an affinity for proSAAS or a peptide fragment, domain or subunit thereof.

47. The composition as claimed in claim 46, wherein the proprotein convertase is selected from the group of proprotein convertases comprising PC1 [also called PC3], PC2, PC4, PC6 [also called PC5], PACE4, LPC [also called PC7 or PC8] and furin.

48. The composition as claimed in claim 12, wherein the effect of the release of proSAAS or peptide fragments, domains or subunits thereof by spherons in the brain is the abnormal processing, post-translational modification or proteolytic cleavage of amyloid precursor protein (APP) or a fragment thereof.

50. The composition as claimed in claim 12, wherein the compound is a peptide fragment, domain or subunit of proprotein convertase 1 (PC1) with an affinity for proSAAS or a peptide fragment, domain or subunit thereof, the compound being an active site selected from the group consisting of:

ENKHG (SEQ ID NO.

     24);

LDGIVTDAIE (SEQ ID NO.

     25);

SWGPNDD (SEQ ID NO.

     26);

WASGNG (SEQ ID NO.

     27);

CDGYTDSIYTI (SEQ ID NO.

     28); and

HTGTS (SEQ ID NO.

     29).

19. A method of identifying compounds useful in treating or ameliorating a neurological condition comprising:

transforming, transfecting or infecting cells, the transformed, transfected or infected cells comprising;

(a) a spheron component peptide other than a spheron component responsible for forming amyloid plaque;

(b) a polynucleotide encoding for a spheron component peptide other than a spheron component responsible for forming amyloid plaque;

or

(c) a polynucleotide that hybridizes under stringent conditions to (b);

administering a test compound to the transformed, transfected or infected cells; and

identifying the compounds that ameliorate the effects of the spheron component other than a spheron component responsible for forming amyloid plaque.

20. The method of claim 19, wherein the spheron component other than a spheron component responsible for forming amyloid plaque is selected from the group consisting of:

a) GEAAGAVQELAR (SEQ ID NO.

     1);

b) GLSAASPPLAETGAPR (SEQ ID NO.

     2);

c) ARAEAQEAEDQQAR (SEQ ID NO.

     3);

d) VLAQLLR (SEQ ID NO.

     4);

e) ALAHLLEAERQER (SEQ ID NO.

     5);

f) AADHDVGSELPPEGVLGALLR (SEQ ID NO.

     6);

g) LETPAPQVPAR (SEQ ID NO.

     7);

h) ILAGSADSEGVAAPR (SEQ ID NO.

     8);

i) ARPVKEPRGLSAASPPLAETGAPRRF (SEQ ID NO.

     9);

j) ARPVKEP (SEQ ID NO.

     10);

k) GLSAASPPLAETGAPRRF (SEQ ID NO.

     11);

l) AADHDVGSELPPEGVLGALLRVKRLETPAPQVPA (SEQ ID NO.

     12);

m) AADHDVGSELPPEGVLGALLRV (SEQ ID NO.

     13);

n) LETPAPQVPA (SEQ ID NO.

     14);

o) RRSVPRGEAAG (SEQ ID NO.

     15);

p) VLAQLLRVWGAPRNSD (SEQ ID NO.

     16);

q) PALGLDDDPDAPAAQLAR (SEQ ID NO.

     17);

r) LARALLRARLDPAALAA (SEQ ID NO.

     18);

s) QLVPAPVPAAALRPRPPVYDD (SEQ ID NO.

     19);

t) GPAGPDAEEAGDE (SEQ ID NO.

     20);

u) TPDVDPELLRYLLGR (SEQ ID NO.

     21);

v) LLRVKR (SEQ ID NO.

     22); and

w) VLGALLRVKRLE (SEQ ID NO.

     23).

21. The method of claim 20, wherein the concentration of the spheron component peptide in the transformed, transfected or infected cells is sufficient to reduce the viability of the cells.

22. The method of claim 20, wherein the transformed, transfected or infected cells are cultured in vitro.

23. The method of claim 20, wherein wherein the transformed, transfected or infected cells are cultured in vivo.

24. The method of claim 20, wherein the test compound is administered to an animal that has been transfected with the transformed, transfected or infected cells.

25. The method of claim 24, further comprising:

preparing an animal model by injecting into the brain of an animal either a gene that expresses one or more of the spheron component peptides other than a spheron component responsible for forming amyloid plaque, or the spheron component peptide; and

inducing the gene to express the spheron component peptide.

26. The method of claim 25, wherein the gene is injected into the brain of the animal along with a vector.

27. A composition comprising a compound selected in accordance with the method of claim 20.

28. The method of claim 25, further comprising:

preparing a group of animal models, each animal model having either;

(i) a gene in the brain thereof that expresses one or more of the spheron component peptides other than a spheron component responsible for forming amyloid plaque;

or (ii) a spheron component peptide having been injected thereto;

inducing the gene if present to express the spheron component peptide;

administering a test compound to the group of animal models;

sacrificing the animals;

measuring the amount of isolated spheron component peptides present in the sacrificed animal'"'"'s brain, and/or measuring the percentage of viable cells at or around the locus of the gene or inserted spheron component peptide; and

selecting those test compounds that reduce the amount of isolated spheron component peptides, when compared to controls, and/or by selecting those test compounds that yield a higher percentage of viable cells at or around the locus of the gene, when compared to controls having no test compound administered thereto.

29. A composition comprising a test compound selected in accordance with the method of claim 28.

30. A method of treating or ameliorating a neurological condition comprising:

administering to an animal in need thereof, a compound that functions in a manner selected from the group consisting of;

a) impedes or prevents the release from a spheron of proSAAS or a peptide fragment, variant, derivative, homologue, or mimetic thereof;

b) binds to, inhibits, antagonizes or competes with proSAAS or a peptide fragment, variant, derivative, homologue, or mimetic thereof that is released from a spheron;

c) reduces or prevents the cytotoxic effects of proSAAS or a peptide fragment, variant, derivative, homologue, or mimetic thereof that is released from a spheron; and

d) counteracts the effects of the release from a spheron component of proSAAS or peptide fragment, variant, derivative, homologue, or mimetic thereof.

31. The method of claim 30, wherein the peptide fragment of proSAAS is one or more peptides selected from the group consisting of:

a) GEAAGAVQELAR (SEQ ID NO.

     1);

b) GLSAASPPLAETGAPR (SEQ ID NO.

     2);

c) ARAEAQEAEDQQAR (SEQ ID NO.

     3);

d) VLAQLLR (SEQ ID NO.

     4);

e) ALAHLLEAERQER (SEQ ID NO.

     5);

f) AADHDVGSELPPEGVLGALLR (SEQ ID NO.

     6);

g) LETPAPQVPAR (SEQ ID NO.

     7);

h) ILAGSADSEGVAAPR (SEQ ID NO.

     8);

i) ARPVKEPRGLSAASPPLAETGAPRRF (SEQ ID NO.

     9);

j) ARPVKEP (SEQ ID NO.

     10);

k) GLSAASPPLAETGAPRRF (SEQ ID NO.

     11);

l) AADHDVGSELPPEGVLGALLRVKRLETPAPQVPA (SEQ ID NO.

     12);

m) AADHDVGSELPPEGVLGALLRV (SEQ ID NO.

     13);

n) LETPAPQVPA (SEQ ID NO.

     14);

o) RRSVPRGEAAG (SEQ ID NO.

     15);

p) VLAQLLRVWGAPRNSD (SEQ ID NO.;

     16);

q) PALGLDDDPDAPAAQLAR (SEQ ID NO.

     17);

r) LARALLRARLDPAALAA (SEQ ID NO.

     18);

s) QLVPAPVPAAALRPRPPVYDD (SEQ ID NO.

     19);

t) GPAGPDAEEAGDE (SEQ ID NO.

     20);

u) TPDVDPELLRYLLGR (SEQ ID NO.

     21);

v) LLRVKR (SEQ ID NO.

     22); and

w) VLGALLRVKRLE (SEQ ID NO.

     23).

32. The method of claim 30, wherein the neurological condition is selected from the group consisting of Alzheimer'"'"'s disease, vascular dimentia, dementia with Lewy bodies, Parkinson'"'"'s disease, Pick'"'"'s disease, Frontotemporal dementia (FTP), and mild cognitive impairment.

33. The method of claim 30, wherein the compound counteracts effects of the release from a spheron component of proSAAS or peptide fragment, variant, derivative, homologue, or mimetic thereof by counteracting the effects of one or more selected from the group consisting of:

a) abnormally inhibited activity of proprotein convertases PC1-PC8 and furin in the brain or in other neuroendocrine tissues caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

b) abnormally decreased adrenocorticotrophic hormone (ACTH) caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

c) abnormally decreased insulin caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

d) abnormally decreased enkephalins caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

e) abnormally decreased thyrotropin-releasing hormone (TRH) caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

f) abnormally decreased dynorphin caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof; and

g) abnormally decreased cerebral α

MSH and β

endorphin, cerebral pro-insulin, cerebral pro-glucagon, cerebral pro-somatostatin, cerebral pro-pancreatic peptide, cerebral pro-GHRH, cerebral neuropeptide melamin-concentrating hormone, cerebral NEI, cerebral neurotensin, and cerebral opioid peptides caused by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof;

34. The method as claimed in claim 33, wherein the compound reduces or counteracts the inhibition of PC1-PC8 and furin.

35. The method as claimed in claim 30, wherein the compound counteracts the effects by the release from spherons in the brain of proSAAS or peptide fragments, variants derivatives, homologues, or mimetics thereof, by increasing at least one component selected from the group consisting of cerebral ACTH, cerebral insulin, cerebral enkephalins, cerebral TRH, cerebral dynorphin cerebral α

MSH, cerebral β

endorphin, cerebral pro-insulin, cerebral pro-glucagon, cerebral pro-somatostatin, cerebral pro-pancreatic peptide, cerebral pro-GHRH, cerebral neuropeptide melamin-concentrating hormone, cerebral NEI, cerebral neurotensin, and cerebral opioid peptides.

36. An animal model comprising an animal having a gene inserted into the brain thereof, whereby the gene expresses proSAAS or one or more spheron component peptides other than a spheron component directly responsible for forming amyloid plaque.

37. The animal model of claim 36, wherein the spheron component other than a spheron component responsible for forming amyloid plaque is selected from the group consisting of:

a) GEAAGAVQELAR (SEQ ID NO.

     1);

b) GLSAASPPLAETGAPR (SEQ ID NO.

     2);

c) ARAEAQEAEDQQAR (SEQ ID NO.

     3);

d) VLAQLLR (SEQ ID NO.

     4);

e) ALAHLLEAERQER (SEQ ID NO.

     5);

f) AADHDVGSELPPEGVLGALLR (SEQ ID NO.

     6);

g) LETPAPQVPAR (SEQ ID NO.

     7);

h) ILAGSADSEGVAAPR (SEQ ID NO.

     8);

i) ARPVKEPRGLSAASPPLAETGAPRRF (SEQ ID NO.

     9);

j) ARPVKEP (SEQ ID NO.

     10);

k) GLSAASPPLAETGAPRRF (SEQ ID NO.

     11);

l) AADHDVGSELPPEGVLGALLRVKRLETPAPQVPA (SEQ ID NO.

     12);

m) AADHDVGSELPPEGVLGALLRV (SEQ ID NO.

     13);

n) LETPAPQVPA (SEQ ID NO.

     14);

o) RRSVPRGEAAG (SEQ ID NO.

     15);

p) VLAQLLRVWGAPRNSD (SEQ ID NO.

     16);

q) PALGLDDDPDAPAAQLAR (SEQ ID NO.

     17);

r) LARALLRARLDPAALAA (SEQ ID NO.

     18);

s) QLVPAPVPAAALRPRPPVYDD (SEQ ID NO.

     19);

t) GPAGPDAEEAGDE (SEQ ID NO.

     20);

u) TPDVDPELLRYLLGR (SEQ ID NO.

     21);

v) LLRVKR (SEQ ID NO.

     22); and

w) VLGALLRVKRLE (SEQ ID NO.

     23).

38. The animal model of claim 36, produced by:

preparing a gene that expresses proSAAS or one or more of spheron component peptides other than a spheron component directly responsible for forming amyloid plaque;

injecting the gene into the brain of the animal; and

inducing the gene to express the proSAAS or one or more of spheron component peptides other than a spheron component directly responsible for forming amyloid plaque.

39. A transformed, transfected or infected cell line comprising recombinant cells that expresses a nucleic acid sequence that encodes proSAAS or a spheron component peptide other than a spheron component responsible for forming amyloid plaque.

40. The cell line of claim 39, wherein the spheron component other than a spheron component responsible for forming amyloid plaque is selected from the group consisting of:

a) GEAAGAVQELAR (SEQ ID NO.

     1);

b) GLSAASPPLAETGAPR (SEQ ID NO.

     2);

c) ARAEAQEAEDQQAR (SEQ ID NO.

     3);

d) VLAQLLR (SEQ ID NO.

     4);

e) ALAHLLEAERQER (SEQ ID NO.

     5);

f) AADHDVGSELPPEGVLGALLR (SEQ ID NO.

     6);

g) LETPAPQVPAR (SEQ ID NO.

     7);

h) ILAGSADSEGVAAPR (SEQ ID NO.

     8);

i) ARPVKEPRGLSAASPPLAETGAPRRF (SEQ ID NO.

     9);

j) ARPVKEP (SEQ ID NO.

     10);

k) GLSAASPPLAETGAPRRF (SEQ ID NO.

     11);

l) AADHDVGSELPPEGVLGALLRVKRLETPAPQVPA (SEQ ID NO.

     12);

m) AADHDVGSELPPEGVLGALLRV (SEQ ID NO.

     13);

n) LETPAPQVPA (SEQ ID NO.

     14); and

o) RRSVPRGEAAG (SEQ ID NO.

     15);

p) VLAQLLRVWGAPRNSD (SEQ ID NO.

     16);

q) PALGLDDDPDAPAAQLAR (SEQ ID NO.

     17);

r) LARALLRARLDPAALAA (SEQ ID NO.

     18);

s) QLVPAPVPAAALRPRPPVYDD (SEQ ID NO.

     19);

t) GPAGPDAEEAGDE (SEQ ID NO.

     20);

u) TPDVDPELLRYLLGR (SEQ ID NO.

     21);

v) LLRVKR (SEQ ID NO.

     22); and

w) VLGALLRVKRLE (SEQ ID NO.

     23).

41. The cell line of claim 39, wherein the nucleic acid sequence comprises:

(a) at least one polynucleotide that encodes any of SEQ ID NOS. 1-23;

or

(b) at least one polynucleotide that hybridizes under stringent conditions to (a).